European Human Genetics Conference (abstract database)
PPARG and PPARGC1A gene variants are associated with height in athletes
I. A. Mozhayskaya, I. I. Ahmetov, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.238
PPARgamma nuclear receptor positively promotes adipogenesis and negatively regulates osteoblast differentiation, indicating that PPARgamma is a negative regulator of bone mass. The Ala12 variant of PPARG gene Pro12Ala polymorphism is associated with lower transcriptional activity, increased body mass index and height in humans. PPARGC1A has been identified as a transcriptional coactivator of PPARgamma. Carriers of the Ser482 allele have been reported to have lower levels of PPARGC1A by comparison with Gly482 allele homozygotes. Therefore, one could expect that the Gly482Ser polymorphism might affect height too. The aim of the study was to investigate an association of PPARG Pro12Ala and PPARG1CA Gly482Ser polymorphisms with height in Russian male rowers and speed skaters. The study involved 99 rowers (height - 191.1 (5.4) cm, weight - 86 (9.7) kg; aged 20-27) and 64 speed skaters (height - 179.6 (6) cm, weight - 74.9 (8.8) kg; aged 20-25). Rowers were divided into three groups: the highest group (195-204 cm), the middle group (189-194 cm) and the lowest group (182-188 cm). Gene polymorphisms were determined by PCR-RLFP. We found that the presence of the PPARG 12Ala allele was significantly associated with higher body height (Ala/Ala+Pro/Ala- 182.7 (4.9) cm vs. Pro/Pro - 178.7 (6.1) cm; P=0.023) in speed skaters. The frequency of the PPARG1CA 482Ser allele was significantly higher in the highest group of rowers (33.3%), than in the middle (22.5%) and the lowest (18.8%) groups (P=0.032). In conclusion, functional polymorphisms in PPARG and PPARG1CA genes may influence the growth of the skeleton in male athletes.
Genome-wide association analysis identifies multiple loci associated with normal variation in height
M. N. Weedon1, H. Lango1, G. Lettre2, .. The GIANT Consortium1,2;
1Peninsula Medical School, Exeter, United Kingdom, 2Broad Institute, Boston, MA, United States.
Presentation Number: P07.060
There are many single gene disorders that affect stature, but little is known about the genetic variants that explain normal variation of adult height. The availability of genome-wide association data offers new opportunities to identify the genes involved in normal growth.
Recent meta-analyses of genome-wide association studies (GWAS), using up to 16,000 individuals, have identified 22 independent loci associated with height (p<5x10-8). The GIANT consortium has now extended these analyses, using imputation methods, to combine association results from 13 GWAS, with a total sample size of >32,000 individuals.
Initial meta-analysis identified 111 independent loci with p<1x10-5 and 50 with p<5x10-7. Confirmed loci implicate a wide range of molecular processes involved in normal growth. These include Hedgehog signaling (PTCH1, HHIP, IHH), chromatin remodeling (SCMH1, HMGA2), and basic cell cycling (CDK6, ANAPC13). Some of the variants and genes have been connected to other diseases, including cancer, suggesting that variants associated with height may also influence disease susceptibility. Many of the associated loci include genes known to be involved in growth based on monogenic human studies. Other loci implicate genes previously unsuspected to have a role in growth, and represent excellent candidate genes for, as yet unexplained, growth-related single gene disorders.
Combining data from many genome-wide association studies is likely to result in the identification of hundreds of loci that influence adult height. These data should result in an unprecedented increase in our knowledge of the genetics of growth and development.
A genome-wide scan of adult human stature and skeletal size
Presentation Time: Tuesday, 10:45 a.m. - 11:00 a.m.
N. Soranzo1, F. Rivadeneira2, U. Chinappen3, M. Inouye1, B. J. Richards3, S. Potter1, R. Gwilliam1, K. Papadakis4, E. Wheeler1, I. Barroso1, D. Hart5, G. Livshits6, R. J. F. Loos7, D. Strachan4, N. J. Wareham7, T. D. Spector3, A. Uitterlinden2, P. Deloukas1;
1The Wellcome Trust Sanger Institute, Hinxton, United Kingdom, 2Erasmus MC, Rotterdam, The Netherlands, 3School of Medicine, King’s College London, London, United Kingdom, 4St George's, University of London, London, United Kingdom, 5St. Thomas' Hospital, London, United Kingdom, 6Tel Aviv University, Tel Aviv, Israel, 7Institute of Metabolic Science, Cambridge, United Kingdom.
Presentation Number: C13.1
Human adult stature is a classical quantitative trait and a paradigm for genetic association studies of quantitative trait variation. We have carried out a meta-analysis of four genome-wide association scans of stature produced using the Illumina HumanHap300 SNP panel in 10,050 adults from four population-based cohorts (TwinsUK, EPIC Norfolk and 1958 Birth Cohort from the UK and the Rotterdam Study from the Netherlands). We have identified eighteen loci showing association with height with P-values of less than 10-5, which we have brought forward for replication in an independent sample of 9,000 individuals.
The signals identified provide strong evidence for replication in genomic regions previously implicated in height, including HMGA2 (rs8756, P-value = 5x10-13) and GDF5-UQCC (rs4911494, P-value = 1.5x10-10). In addition, we have identified novel candidate genetic loci for human height, some of which are in or near genes implicated in cellular growth and development (HHIP, ADAMTSL3 and DLEU7). In an attempt to dissect the mechanisms underlying human growth, we have tested the association of these novel candidate height loci with different measurements of skeletal growth. Our results provide both novel and confirmatory evidence for the implication of genes and pathways in human growth, thus contributing to the understanding of the biological processes underlying many common and severe human diseases.
Genome wide association analysis in human height of European-originated monozygotic female twins
J. A. Kettunen1,2, I. Lindqvist2, S. Ripatti2,3, T. D. Spector4, N. G. Martin5, L. Peltonen1,2, M. Perola2;
1Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2National Public Health Institute, Helsinki, Finland, 3Karolinska Institutet, Stockholm, Sweden, 4Twin Research and Genetic Epidemiology Unit, King's College, London, United Kingdom, 5Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Austria.
Presentation Number: P06.126
Stature (i.e. adult height) is a quantitative trait with high heritability. Various interesting regions in the human genome have been linked to adult stature but only few have been confirmed by later studies. Two genome wide association (GWA) studies have been published recently and they identified two loci (HMGA2 and GDF5-UQCC) to be strongly associated to stature after extensive replication studies. In this study we report a genome wide association analysis performed on 1631 European monozygotic female twin pairs from the GenomEUtwin consortium. One of each pair was genotyped with the Illumina HumanHap300-duo chip. Whole genome association analysis was performed with the PLINK-program. Area of residence and age were used as covariates in all of the analyses. Our study had two goals: We wanted to reduce the environmental variance by using the mean of each pair as a phenotype. We observed an association (p = 3.14*10-6) on 8q24 locus underlying the linkage peak identified previously in our linkage scan on European dizygotic twins (LOD 3.28). The replication study is underway for the most significant findings in this GWA scan. Second, we analyzed whether we could pinpoint any regions in genome which would be associated to the difference within each pair. This approach was aiming to find genes responsible for increasing variance in human height, thus potentially indicating for example GxE interaction or imprinting/gene silencing. The most significant finding for variance in stature (p = 1.22 * 10-5) was identified on 6q14 region.
Genetic analysis of adult stature in Dutch isolated population
I. V. Zorkoltseva1, T. I. Axenovich1, C. M. van Duijn2;
1Institute of Cytology and Genetics, Novosibirsk, Russian Federation, 2Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, Netherlands.
Presentation Number: P06.008
We analysed a large complex pedigree from a Dutch genetically isolated population. About 2600 of 19700 pedigree members were phenotyped and genotyped for autosomal 5208 SNPs (Illumina 6K linkage panel). Complex segregation analysis of adult height was performed under mixed model including effects of biallelic major gene, polygene, age and sex. We used likelihood approximation based on breaking pedigree loops. The results confirmed large contribution of genes in the trait variance (h2 = 0.85 ) and significance of major gene effect in accordance with Elston-Stewart test. Three genotypic means were estimated as 183.5, 178.3 and 174.6 cm in males at 40 years with average difference of male and female genotypic means about 13 cm. The putative major gene explained 18% of trait variance.
A genome-wide scan was performed by variance-components method using Merlin program. Prior to analysis, the pedigree was split into smaller non-overlapping fragments, with maximum bit-size of 18. No loci demonstrated significant linkage, however for 6 loci linkage was suggestive:
SNP Chr Position(cM) LodScore
rs1993104 19 56.9 2.71
rs1873191 18 44.7 2.60
rs1019845 2 195.8 2.27
rs958883 5 123.3 2.15
rs936347 16 17.2 2.11
rs216223 17 2.1 2.11
Of these six loci, five were identified in previous linkage analyses, while locus at chromosome 16 (rs936347) was new.
Showing posts with label ESHG 2008. Show all posts
Showing posts with label ESHG 2008. Show all posts
Longevity (ESHG 2008 abstracts)
European Human Genetics Conference (abstract database)
The relation of common diseases SNPs and life span: no evidence for shared genetic component
O. Y. Byichkova1, O. A. Makeeva1, I. V. Tsimbal'uk2, K. V. Puzyrev3, V. N. Maksimov4, V. P. Puzyrev1,2;
1Research Institute of Medical Genetics, Tomsk, Russian Federation, 2Siberian State Medical University, Tomsk, Russian Federation, 3Research Institute of Cardiology, Tomsk, Russian Federation, 4Research Institute of Therapy, Novosibirsk, Russian Federation.
Presentation Number: P07.028
Life span is a multifactorial trait with a strong genetic component. Besides the number of genes has been directly implicated into the processes of ageing and longevity, the genes responsible for common diseases such as cardiovascular (CVD) or immunity disorders are also had to be under intent consideration. The persistence and both elimination from human populations ‘predisposing’ common genetic variants is forced by a complex interplay of different evolutionary processes; some variants being unfavorable during particular periods of life can offer their owners advantages on the others. Latter should be taken into account e.g. while developing genetic test and interpreting frequently discrepant genetic data on disease association. Testing the hypothesis that CVD predisposing alleles can be related to the life span, we investigate several cohorts: healthy controls of childbearing age (aged from 20 to 45, n=282), nonagenarians (aged 90 and over, n=235) and patients with cardiovascular disease (arterial hypertension with different complications) (n=231) from the same geographic region and ethnicity (East Siberia, Russians) and genotyped for several well-known CVD candidate genes polymorphisms (G-308A TNF, C894T NOS3, and A1166C AGTR1). While all the three SNPs under study affected several important cardiovascular endophenotypes (arterial blood pressure measurements, cardiac parameters, left ventricular hypertrophy development est.) no significant differences had been revealed among nonagenarians and middle aged group. In this study we never found actual proof for the stated hypothesis, though a huge amount of other genetic variants and the larger samples are needed to be tested before its decline.
Age-dependent genetic polymorphism frequencies and Gene - Pass
V. S. Baranov1, H. V. Baranova2, O. S. Glotov1;
1Ott’s Institute of Obstetrics & Gynecology, St.Petersburg, Russian Federation, 2European Institute of Personalized Prevention, Nice, France.
Presentation Number: P07.058
The report highlights the results of collaborative studies of personalized anti-aging medicine and its impact into longevity and aging. Special attention is paid to the gene nets of cardiovascular diseases, renin-angiotensin system, diabetus mellitus, osteoporosis etc. Polymorphic variants of at least some particular genes such as ACE, AGT, PAII, MTHFR, APOE, also as metabolic genes, like GSTs and other oxidative stress markers (NOS) are considered as the most plausible candidates of the genes crucial for aging. Molecular analysis of these particular genes supplemented with relevant metabolic genes testing, responsible for efficiency of detoxification system might have substantial contribution into personalyzed anti - aging medicine. The data on allele frequencies distribution for 10 differenet genes in newborns (106), 119 middle age and 148 old people over 69 are presented Relevant gene testing supplemented with its adequate sophisticated interpretation and constructive recommendations might have substantial contribution to human health and should be considered as a new highly promising tool in anti-aging medicine “Gene - pass ” term is suggested for the individual DNA data bank reflecting increased personal susceptibility to these common disorders. Tremendous impact to its practical application could be achieved through wide scale application of biochip technology. The latter are already available or are in progress for a number of multifactorial diseases. Special attention is paid to Genetic Pass of Reproductive Health - a version of Genetic Pass adjusted to the needs of pregnant woman. Life in harmony with personal gene makeup remains indispensable prerequisite of longevity and good health..
Study on a possible effect of four longevity candidate genes (ACE, PON1, PPAR-gamma, APOE) on human fertility
R. M. Corbo1,2, L. Ulizzi1, L. Piombo1, R. Scacchi2;
1La Sapienza University, Rome, Italy, 2CNR Institute of Molecular Biology and Pathology, Rome, Italy.
Presentation Number: P07.080
A possible effect on fertility of four genes [angiotensin 1-converting enzyme (ACE), paraoxonase (PON1), peroxisome proliferator-activated receptor gamma (PPAR-g), and apolipoprotein E(APOE)] previously found associated with longevity was sought in order to determine whether they have a pleiotropic action at different life ages. The study population was 151 Italian subjects whose reproductive life took place at the beginning of the demographic transition (declining fertility and longer life expectancy) and who had produced a mean number of children (3.6±2.3) such as to be still useful to detect a differential reproductive efficiency associated with different genotypes.
Of these four longevity candidate genes, only PPAR-g and APOE appeared to have an effect on fertility, indicating their possible influence on reproductive efficiency. The PPAR-g Pro/Ala genotype, which in a previous study (Barbieri et el. 2004) showed a positive association with longevity only in men, was found associated with a higher number of children (6.1 ± 3.3) than Pro/Pro genotype (3.3 ± 1.9, p=0.001) only in men. Compared with the other APOE alleles, the APOE*2 allele, considered as an allele favouring a longer life-span, was confirmed to be associated with the lowest fertility (p=0.03). The logistic regression analysis indicated that APOE and PPAR-g polymorphisms act as independent determinants of reproductive efficiency. These data suggest that the APOE*2 allele may follow the model of antagonist pleiotropy, whereas the PPAR-g Pro/Ala genotype seems to exert beneficial effects both early in life and in advanced age in a gender-specific way.
The relation of common diseases SNPs and life span: no evidence for shared genetic component
O. Y. Byichkova1, O. A. Makeeva1, I. V. Tsimbal'uk2, K. V. Puzyrev3, V. N. Maksimov4, V. P. Puzyrev1,2;
1Research Institute of Medical Genetics, Tomsk, Russian Federation, 2Siberian State Medical University, Tomsk, Russian Federation, 3Research Institute of Cardiology, Tomsk, Russian Federation, 4Research Institute of Therapy, Novosibirsk, Russian Federation.
Presentation Number: P07.028
Life span is a multifactorial trait with a strong genetic component. Besides the number of genes has been directly implicated into the processes of ageing and longevity, the genes responsible for common diseases such as cardiovascular (CVD) or immunity disorders are also had to be under intent consideration. The persistence and both elimination from human populations ‘predisposing’ common genetic variants is forced by a complex interplay of different evolutionary processes; some variants being unfavorable during particular periods of life can offer their owners advantages on the others. Latter should be taken into account e.g. while developing genetic test and interpreting frequently discrepant genetic data on disease association. Testing the hypothesis that CVD predisposing alleles can be related to the life span, we investigate several cohorts: healthy controls of childbearing age (aged from 20 to 45, n=282), nonagenarians (aged 90 and over, n=235) and patients with cardiovascular disease (arterial hypertension with different complications) (n=231) from the same geographic region and ethnicity (East Siberia, Russians) and genotyped for several well-known CVD candidate genes polymorphisms (G-308A TNF, C894T NOS3, and A1166C AGTR1). While all the three SNPs under study affected several important cardiovascular endophenotypes (arterial blood pressure measurements, cardiac parameters, left ventricular hypertrophy development est.) no significant differences had been revealed among nonagenarians and middle aged group. In this study we never found actual proof for the stated hypothesis, though a huge amount of other genetic variants and the larger samples are needed to be tested before its decline.
Age-dependent genetic polymorphism frequencies and Gene - Pass
V. S. Baranov1, H. V. Baranova2, O. S. Glotov1;
1Ott’s Institute of Obstetrics & Gynecology, St.Petersburg, Russian Federation, 2European Institute of Personalized Prevention, Nice, France.
Presentation Number: P07.058
The report highlights the results of collaborative studies of personalized anti-aging medicine and its impact into longevity and aging. Special attention is paid to the gene nets of cardiovascular diseases, renin-angiotensin system, diabetus mellitus, osteoporosis etc. Polymorphic variants of at least some particular genes such as ACE, AGT, PAII, MTHFR, APOE, also as metabolic genes, like GSTs and other oxidative stress markers (NOS) are considered as the most plausible candidates of the genes crucial for aging. Molecular analysis of these particular genes supplemented with relevant metabolic genes testing, responsible for efficiency of detoxification system might have substantial contribution into personalyzed anti - aging medicine. The data on allele frequencies distribution for 10 differenet genes in newborns (106), 119 middle age and 148 old people over 69 are presented Relevant gene testing supplemented with its adequate sophisticated interpretation and constructive recommendations might have substantial contribution to human health and should be considered as a new highly promising tool in anti-aging medicine “Gene - pass ” term is suggested for the individual DNA data bank reflecting increased personal susceptibility to these common disorders. Tremendous impact to its practical application could be achieved through wide scale application of biochip technology. The latter are already available or are in progress for a number of multifactorial diseases. Special attention is paid to Genetic Pass of Reproductive Health - a version of Genetic Pass adjusted to the needs of pregnant woman. Life in harmony with personal gene makeup remains indispensable prerequisite of longevity and good health..
Study on a possible effect of four longevity candidate genes (ACE, PON1, PPAR-gamma, APOE) on human fertility
R. M. Corbo1,2, L. Ulizzi1, L. Piombo1, R. Scacchi2;
1La Sapienza University, Rome, Italy, 2CNR Institute of Molecular Biology and Pathology, Rome, Italy.
Presentation Number: P07.080
A possible effect on fertility of four genes [angiotensin 1-converting enzyme (ACE), paraoxonase (PON1), peroxisome proliferator-activated receptor gamma (PPAR-g), and apolipoprotein E(APOE)] previously found associated with longevity was sought in order to determine whether they have a pleiotropic action at different life ages. The study population was 151 Italian subjects whose reproductive life took place at the beginning of the demographic transition (declining fertility and longer life expectancy) and who had produced a mean number of children (3.6±2.3) such as to be still useful to detect a differential reproductive efficiency associated with different genotypes.
Of these four longevity candidate genes, only PPAR-g and APOE appeared to have an effect on fertility, indicating their possible influence on reproductive efficiency. The PPAR-g Pro/Ala genotype, which in a previous study (Barbieri et el. 2004) showed a positive association with longevity only in men, was found associated with a higher number of children (6.1 ± 3.3) than Pro/Pro genotype (3.3 ± 1.9, p=0.001) only in men. Compared with the other APOE alleles, the APOE*2 allele, considered as an allele favouring a longer life-span, was confirmed to be associated with the lowest fertility (p=0.03). The logistic regression analysis indicated that APOE and PPAR-g polymorphisms act as independent determinants of reproductive efficiency. These data suggest that the APOE*2 allele may follow the model of antagonist pleiotropy, whereas the PPAR-g Pro/Ala genotype seems to exert beneficial effects both early in life and in advanced age in a gender-specific way.
Structural variation (ESHG 2008 abstracts)
European Human Genetics Conference (abstract database)
Genomic structural variation profiles of world human populations
Presentation Time: Saturday, 7:30 p.m. - 7:45 p.m.
L. Bassaganyas1,2,3, M. Garcia1,3, M. Montfort1,4,3, L. Armengol1,3, X. Estivill1,4,3;
1Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain, 2Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, 3Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Catalonia, Spain, 4National Genotyping Center (CeGen), Barcelona, Catalonia, Spain.
Presentation Number: PL2.5
Genomic variants can contribute to genetic disease, and are potential substrates for natural selection resulting in phenotypic differences between individuals. The use of genome-wide molecular methods have revealed the existence of Copy Number Variants (CNVs), genomic segments ranging in size from one kb to several megabases, that are present at variable copy number in comparison with a reference genome. The aim of our study was to determine the existence of population-specific genomic structural variation and to identify genes located in these regions that might contribute to phenotypic differences as well as to differential susceptibility to common disease and environmental exposures of human populations. We have selected 343 individuals from 11 populations from the HGDP-CEPH panel (Biaka- Mbuti Pygmy, Bantu, Mozabite, Bedouin, Brahui, Hazara, Yakut, Papuan-Melanesian, French, Pima and Maya) and 134 individuals from the three populations of the HapMap collection (YRI, CHB and CEU). To detect structural variation we have used array-CGH (Agilent 244K) and array-based comparative genome intensity (Illumina). We have observed differences between populations in 179 loci. 122 of these were already described in the Database of Genomic Variants and 58 coincide with segmental duplications. Interestingly, a number of genes involved in different common disorders or to have phenotypic differences between population groups were found to be variable in copy number among human populations (i.e. RHD, CFHR1, CFHR3 and PRSS1). These loci and others could explain differences in disease predisposition among individuals from different populations and could provide important clues on the adaptation of humans to different environments.
A full survey of common copy number variation in the human genome
Presentation Time: Tuesday, 11:15 a.m. - 11:30 a.m.
R. Redon1, D. F. Conrad1, L. Feuk2, C. Lee3, S. W. Scherer2, M. E. Hurles1, N. P. Carter1;
1Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Brigham and Women’s Hospital, Boston, MA, United States.
Presentation Number: C13.3
Copy number variation (CNV) in the genome is extensive and yet is grossly under-ascertained. As smaller CNVs are expected to be far more numerous than larger CNVs, improved CNV detection resolution will dramatically increase the numbers of known CNVs. The Genome Structural Variation Consortium has performed comparative genome hybridisation on a genome-wide set of tiling oligonucleotide arrays to discover the majority of common copy number variants >500bp in size in two populations with African and European ancestry. This set covers the assayable portion of the human genome with 42,000,000 probes with a median spacing of ~50bp. In addition we have generated data on a single chimpanzee to provide information on the ancestral state of observed variants. The results reveal, as expected, that previous surveys captured only 5-10% of the CNVs within a single genome. Because the boundaries of thousands of CNVs are defined precisely by this probe set, we can identify accurately functional sequences included in copy number variable regions. This provides new insights into the mechanisms generating chromosomal rearrangements and the biological functions of common CNVs.
A high-resolution structural variation map of a human genome by next-generation, high-throughput paired-end sequencing
Presentation Time: Sunday, 3:15 p.m. - 3:30 p.m.
F. M. De La Vega1, H. E. Peckham2, S. S. Ranade2, S. F. McLaughlin2, C. C. Lee2, Y. Fu2, Z. Zhang1, F. C. L. Hyland1, C. L. Clouser2, A. A. Antipova2, J. M. Manning2, C. L. Hendrickson2, L. Zhang2, E. T. Dimalanta2, T. D. Sokolsky2, M. W. Laptewicz2, B. E. Coleman2, J. K. Ichikawa2, J. B. Warner2, B. Li1, J. M. Kidd3, J. A. Malek4, G. L. Costa2, E. E. Eichler3, K. J. McKernan2;
1Applied Biosystems, Foster City, CA, United States, 2Applied Biosystems, Beverly, MA, United States, 3HHMI, University of Washington, Seattle, WA, United States, 4Weill Cornell Medical College in Qatar, Doha, Qatar.
Presentation Number: C05.2
The human genome and HapMap projects have considerably increased our understanding of the role of sequence variation in evolution and disease. Hybridization microarrays and fosmid-end sequencing reveal that structural variants (SVs) including insertions, deletions, duplications, inversions and translocations are common and extensive. Microarray methods, however, lack resolution and are blind to unbalanced events, while clone-based end-sequencing is time consuming and expensive. Here, we present a high-resolution survey of SVs of a human genome, a HapMap Yoruba sample (NA18507), by ultra-high throughput sequencing of paired-end libraries with the AB SOLiD(TM) System. We sequenced a variety of 2x25-bp paired-end libraries (>15Gb) with insert sizes ranging from 600bp to 6kb (SD 10-23%). Each library provides over 10x physical (clone) coverage, with a total combined physical coverage >60x for 90% of the genome. The high physical coverage and diverse insert sizes allowed detecting small indels within tags (1-10 bp), and approximately 70,000 indels of length 20 bp to >100 kb. Additionally, we sequenced 7Gb of 50-bp fragment libraries, which combined with the paired libraries provided over 12x sequence coverage, allowing us to discover millions of SNPs of which 75% are found in dbSNP. Inferred SVs were compared to a database of end-sequence pairs of 10x physical coverage obtained by di-deoxy sequencing of 40kb fosmid ends. A subset of novel SVs were validated by PCR and Sanger sequencing. Our results serves as a model for further high-resolution exploration of genetic variation in human populations and cancer with next-generation sequencing.
Genomic structural variation profiles of world human populations
Presentation Time: Saturday, 7:30 p.m. - 7:45 p.m.
L. Bassaganyas1,2,3, M. Garcia1,3, M. Montfort1,4,3, L. Armengol1,3, X. Estivill1,4,3;
1Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain, 2Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, 3Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Catalonia, Spain, 4National Genotyping Center (CeGen), Barcelona, Catalonia, Spain.
Presentation Number: PL2.5
Genomic variants can contribute to genetic disease, and are potential substrates for natural selection resulting in phenotypic differences between individuals. The use of genome-wide molecular methods have revealed the existence of Copy Number Variants (CNVs), genomic segments ranging in size from one kb to several megabases, that are present at variable copy number in comparison with a reference genome. The aim of our study was to determine the existence of population-specific genomic structural variation and to identify genes located in these regions that might contribute to phenotypic differences as well as to differential susceptibility to common disease and environmental exposures of human populations. We have selected 343 individuals from 11 populations from the HGDP-CEPH panel (Biaka- Mbuti Pygmy, Bantu, Mozabite, Bedouin, Brahui, Hazara, Yakut, Papuan-Melanesian, French, Pima and Maya) and 134 individuals from the three populations of the HapMap collection (YRI, CHB and CEU). To detect structural variation we have used array-CGH (Agilent 244K) and array-based comparative genome intensity (Illumina). We have observed differences between populations in 179 loci. 122 of these were already described in the Database of Genomic Variants and 58 coincide with segmental duplications. Interestingly, a number of genes involved in different common disorders or to have phenotypic differences between population groups were found to be variable in copy number among human populations (i.e. RHD, CFHR1, CFHR3 and PRSS1). These loci and others could explain differences in disease predisposition among individuals from different populations and could provide important clues on the adaptation of humans to different environments.
A full survey of common copy number variation in the human genome
Presentation Time: Tuesday, 11:15 a.m. - 11:30 a.m.
R. Redon1, D. F. Conrad1, L. Feuk2, C. Lee3, S. W. Scherer2, M. E. Hurles1, N. P. Carter1;
1Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Brigham and Women’s Hospital, Boston, MA, United States.
Presentation Number: C13.3
Copy number variation (CNV) in the genome is extensive and yet is grossly under-ascertained. As smaller CNVs are expected to be far more numerous than larger CNVs, improved CNV detection resolution will dramatically increase the numbers of known CNVs. The Genome Structural Variation Consortium has performed comparative genome hybridisation on a genome-wide set of tiling oligonucleotide arrays to discover the majority of common copy number variants >500bp in size in two populations with African and European ancestry. This set covers the assayable portion of the human genome with 42,000,000 probes with a median spacing of ~50bp. In addition we have generated data on a single chimpanzee to provide information on the ancestral state of observed variants. The results reveal, as expected, that previous surveys captured only 5-10% of the CNVs within a single genome. Because the boundaries of thousands of CNVs are defined precisely by this probe set, we can identify accurately functional sequences included in copy number variable regions. This provides new insights into the mechanisms generating chromosomal rearrangements and the biological functions of common CNVs.
A high-resolution structural variation map of a human genome by next-generation, high-throughput paired-end sequencing
Presentation Time: Sunday, 3:15 p.m. - 3:30 p.m.
F. M. De La Vega1, H. E. Peckham2, S. S. Ranade2, S. F. McLaughlin2, C. C. Lee2, Y. Fu2, Z. Zhang1, F. C. L. Hyland1, C. L. Clouser2, A. A. Antipova2, J. M. Manning2, C. L. Hendrickson2, L. Zhang2, E. T. Dimalanta2, T. D. Sokolsky2, M. W. Laptewicz2, B. E. Coleman2, J. K. Ichikawa2, J. B. Warner2, B. Li1, J. M. Kidd3, J. A. Malek4, G. L. Costa2, E. E. Eichler3, K. J. McKernan2;
1Applied Biosystems, Foster City, CA, United States, 2Applied Biosystems, Beverly, MA, United States, 3HHMI, University of Washington, Seattle, WA, United States, 4Weill Cornell Medical College in Qatar, Doha, Qatar.
Presentation Number: C05.2
The human genome and HapMap projects have considerably increased our understanding of the role of sequence variation in evolution and disease. Hybridization microarrays and fosmid-end sequencing reveal that structural variants (SVs) including insertions, deletions, duplications, inversions and translocations are common and extensive. Microarray methods, however, lack resolution and are blind to unbalanced events, while clone-based end-sequencing is time consuming and expensive. Here, we present a high-resolution survey of SVs of a human genome, a HapMap Yoruba sample (NA18507), by ultra-high throughput sequencing of paired-end libraries with the AB SOLiD(TM) System. We sequenced a variety of 2x25-bp paired-end libraries (>15Gb) with insert sizes ranging from 600bp to 6kb (SD 10-23%). Each library provides over 10x physical (clone) coverage, with a total combined physical coverage >60x for 90% of the genome. The high physical coverage and diverse insert sizes allowed detecting small indels within tags (1-10 bp), and approximately 70,000 indels of length 20 bp to >100 kb. Additionally, we sequenced 7Gb of 50-bp fragment libraries, which combined with the paired libraries provided over 12x sequence coverage, allowing us to discover millions of SNPs of which 75% are found in dbSNP. Inferred SVs were compared to a database of end-sequence pairs of 10x physical coverage obtained by di-deoxy sequencing of 40kb fosmid ends. A subset of novel SVs were validated by PCR and Sanger sequencing. Our results serves as a model for further high-resolution exploration of genetic variation in human populations and cancer with next-generation sequencing.
Ancestry analysis (ESHG 2008 abstracts)
European Human Genetics Conference (abstract database)
The genome-wide patterns of variation confirms significant substructure in a founder population
K. Rehnström1,2, E. Jakkula1,3, T. Varilo1,2, O. Pietiläinen1, T. Paunio1, N. Pedersen4, M. Järvelin5, S. Ripatti1,4, S. Purcell3, M. Daly3, A. Palotie3,6, L. Peltonen1,6;
1National Public Health Institute, Helsinki, Finland, 2University of Helsinki, Helsinki, Finland, 3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, United States, 4Karolinska Institute, Stockholm, Sweden, 5Imperial College, London, United Kingdom, 6Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Presentation Number: P07.051
The genome-wide SNP genotyping platforms enable detailed association studies, but at the same time offer new insight into population genetics. Here we present an example of a founder population by scrutinizing nine geographically distinct Finnish subpopulations representing different eras in the population history to study the effect of bottlenecks and isolation using high-density SNP data. We demonstrate that population substructure and even individual ancestry are detectable at high resolution and support the concept of multiple historical bottlenecks resulting from founder effects.
We performed multidimensional scaling (MDS) of pairwise identity-by state (IBS) sharing data to delineate population structure. Within Finland the two primary dimensions of the MDS-analysis correspond remarkably with the east-west and north-south directions, respectively, showing a distribution of individuals corresponding closely with the geographical distribution of parents’ birthplaces. The youngest subisolates showed higher IBS similarity compared to other subgroups and separation using an extremely fine resolution. We analyzed linkage disequilibrium (LD) and extended regions of homozygosity (ROHs) to further explore the genomic structure of the subpopulations. Highest LD and the largest number of long (>10Mb) ROHs was identified in the youngest regional population and showed a gradual decline of these measures in older and more outbred, subpopulations.
The study shows the power of GWA data to trace the population history and also exemplifies the power to identify stratification even within homogeneous populations. A deeper insight into fine-scale population substructure also emphasizes the importance of adjustment of GWA studies aiming at identifying smaller and smaller genetic effects to avoid confounding.
Comparison of different methods to estimate genetic ancestry and control for stratification in genome-wide association studies
Presentation Time: Tuesday
E. Salvi1,2, G. Guffanti1, A. Orro2, F. Torri1, S. Lupoli3, J. Turner4, D. Keator4, J. Fallon4, S. Potkin4, C. Barlassina1, D. Cusi1, L. Milanesi2, F. Macciardi1;
1Department of Science and Biomedical Technology, University of Milan, Milan, Italy, 2ITB CNR, Segrate, Milan, Italy, 3INSPE, Milan, Italy, 4Department of Psychiatry and Human Behavior University of California, Irvine, CA, United States.
Presentation Number: C13.6
In case-control association studies, population subdivision or admixture can lead to spurious associations between a phenotype and unlinked candidate loci. Population stratification can occur in case-control association studies when allele frequencies differ between cases and controls because of ancestry.
We evaluated five methods (Fst, Genomic Control, STRUCTURE, PLINK and EIGENSTRAT) using 317K SNPs (Illumina HumanHap300) in a case-control sample of 200 American subjects with different races (Caucasian, African and Asian) in order to identify and to correct for stratification. Fst, Structure and Genomic Control are based on the usage of few genetic markers while PLINK and EIGENSTRAT are computationally tractable on a genome-wide scale. Fst, STRUCTURE and Genomic Control did not detect a significant stratification in our sample, as well as EIGENSTRAT and PLINK. However, these last two methods, using a much larger information from the whole set of SNPs, graphically suggested the presence of a partial stratification, due to African and Asian individuals while the estimated inflation factor of 1 didn't statistically confirm stratification. This brought to the decision to further enlarge the sample with hundreds of controls coming from Caucasian populations. When we enlarged the sample to 650 individuals we found a high value of inflation factor as statistical confirmation of the population stratification. The substructure still depends only on African and Asian subjects that are separated from the Caucasian homogeneous sample. Therefore the sample size is crucial to get enough power to detect a possible stratification.
A computational test for biological relatedness in genetic association studies using probabilistically inferred haplotypes
L. Xumerle, G. Malerba, P. F. Pignatti;
Department Maternal Infantile and of Biology-Genetics. Section of Biology and Genetics, University of Verona, Italy.
Presentation Number: P06.058
An association between gene and disease may be incorrectly estimated if the allele frequencies differ among cases and controls depending on inbreeding or unrecognized population stratification.
A program (http://medgen.univr.it/jenoware/) was developed to compute the probability of genetic relatedness in pairs of individuals using a likelihood ratio test.
Using loci that are in LD decreases the accuracy of parentage assignments. Groups of SNPs in linkage disequilibrium (LD) were simulated to verify the effects of linkage on relatedness assignment. The probability of genetic relatedness was computed using the single SNPs and treating the SNPs as composite markers with different r² threshold values. Haplotypes were probabilistically inferred using the PHASE and Gerbil programs. False positive rate and power were assessed by simulation in unrelated individuals and in pedigrees.
As an example of results, in order to estimate the support for II degree relatedness with power 80%, and false positive rate 5%, the following was needed: 100 SNPs with no linkage; 275 SNPs having r²=0.4; 20 probabilistically inferred haplotypes (100 SNPs having r²=0.4); 40 probabilistically inferred haplotypes (200 SNPs having r²=0.8).
In conclusion, if LD blocks are examined, the biological relatedness can be computed with a limited number of markers increasing test accuracy with probabilistically inferred haplotypes.
The genome-wide patterns of variation confirms significant substructure in a founder population
K. Rehnström1,2, E. Jakkula1,3, T. Varilo1,2, O. Pietiläinen1, T. Paunio1, N. Pedersen4, M. Järvelin5, S. Ripatti1,4, S. Purcell3, M. Daly3, A. Palotie3,6, L. Peltonen1,6;
1National Public Health Institute, Helsinki, Finland, 2University of Helsinki, Helsinki, Finland, 3Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, United States, 4Karolinska Institute, Stockholm, Sweden, 5Imperial College, London, United Kingdom, 6Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Presentation Number: P07.051
The genome-wide SNP genotyping platforms enable detailed association studies, but at the same time offer new insight into population genetics. Here we present an example of a founder population by scrutinizing nine geographically distinct Finnish subpopulations representing different eras in the population history to study the effect of bottlenecks and isolation using high-density SNP data. We demonstrate that population substructure and even individual ancestry are detectable at high resolution and support the concept of multiple historical bottlenecks resulting from founder effects.
We performed multidimensional scaling (MDS) of pairwise identity-by state (IBS) sharing data to delineate population structure. Within Finland the two primary dimensions of the MDS-analysis correspond remarkably with the east-west and north-south directions, respectively, showing a distribution of individuals corresponding closely with the geographical distribution of parents’ birthplaces. The youngest subisolates showed higher IBS similarity compared to other subgroups and separation using an extremely fine resolution. We analyzed linkage disequilibrium (LD) and extended regions of homozygosity (ROHs) to further explore the genomic structure of the subpopulations. Highest LD and the largest number of long (>10Mb) ROHs was identified in the youngest regional population and showed a gradual decline of these measures in older and more outbred, subpopulations.
The study shows the power of GWA data to trace the population history and also exemplifies the power to identify stratification even within homogeneous populations. A deeper insight into fine-scale population substructure also emphasizes the importance of adjustment of GWA studies aiming at identifying smaller and smaller genetic effects to avoid confounding.
Comparison of different methods to estimate genetic ancestry and control for stratification in genome-wide association studies
Presentation Time: Tuesday
E. Salvi1,2, G. Guffanti1, A. Orro2, F. Torri1, S. Lupoli3, J. Turner4, D. Keator4, J. Fallon4, S. Potkin4, C. Barlassina1, D. Cusi1, L. Milanesi2, F. Macciardi1;
1Department of Science and Biomedical Technology, University of Milan, Milan, Italy, 2ITB CNR, Segrate, Milan, Italy, 3INSPE, Milan, Italy, 4Department of Psychiatry and Human Behavior University of California, Irvine, CA, United States.
Presentation Number: C13.6
In case-control association studies, population subdivision or admixture can lead to spurious associations between a phenotype and unlinked candidate loci. Population stratification can occur in case-control association studies when allele frequencies differ between cases and controls because of ancestry.
We evaluated five methods (Fst, Genomic Control, STRUCTURE, PLINK and EIGENSTRAT) using 317K SNPs (Illumina HumanHap300) in a case-control sample of 200 American subjects with different races (Caucasian, African and Asian) in order to identify and to correct for stratification. Fst, Structure and Genomic Control are based on the usage of few genetic markers while PLINK and EIGENSTRAT are computationally tractable on a genome-wide scale. Fst, STRUCTURE and Genomic Control did not detect a significant stratification in our sample, as well as EIGENSTRAT and PLINK. However, these last two methods, using a much larger information from the whole set of SNPs, graphically suggested the presence of a partial stratification, due to African and Asian individuals while the estimated inflation factor of 1 didn't statistically confirm stratification. This brought to the decision to further enlarge the sample with hundreds of controls coming from Caucasian populations. When we enlarged the sample to 650 individuals we found a high value of inflation factor as statistical confirmation of the population stratification. The substructure still depends only on African and Asian subjects that are separated from the Caucasian homogeneous sample. Therefore the sample size is crucial to get enough power to detect a possible stratification.
A computational test for biological relatedness in genetic association studies using probabilistically inferred haplotypes
L. Xumerle, G. Malerba, P. F. Pignatti;
Department Maternal Infantile and of Biology-Genetics. Section of Biology and Genetics, University of Verona, Italy.
Presentation Number: P06.058
An association between gene and disease may be incorrectly estimated if the allele frequencies differ among cases and controls depending on inbreeding or unrecognized population stratification.
A program (http://medgen.univr.it/jenoware/) was developed to compute the probability of genetic relatedness in pairs of individuals using a likelihood ratio test.
Using loci that are in LD decreases the accuracy of parentage assignments. Groups of SNPs in linkage disequilibrium (LD) were simulated to verify the effects of linkage on relatedness assignment. The probability of genetic relatedness was computed using the single SNPs and treating the SNPs as composite markers with different r² threshold values. Haplotypes were probabilistically inferred using the PHASE and Gerbil programs. False positive rate and power were assessed by simulation in unrelated individuals and in pedigrees.
As an example of results, in order to estimate the support for II degree relatedness with power 80%, and false positive rate 5%, the following was needed: 100 SNPs with no linkage; 275 SNPs having r²=0.4; 20 probabilistically inferred haplotypes (100 SNPs having r²=0.4); 40 probabilistically inferred haplotypes (200 SNPs having r²=0.8).
In conclusion, if LD blocks are examined, the biological relatedness can be computed with a limited number of markers increasing test accuracy with probabilistically inferred haplotypes.
Brain / mind (ESHG 2008 abstracts)
European Human Genetics Conference (abstract database)
Associations between serotonin transporter gene SLC6A4 polymorphism and level of intellectual development (IQ) of the person
O. Gumerova, E. V. Lekontsev, V. Y. Gorbunova;
Bashkir State Pedagogical University it. M. Akmulla, Ufa, Russian Federation.
Presentation Number: P07.100
INTRODUCTION: Serotonin transporter gene SLC6A4 (17q11.1-12) is one of the basic genes, which define an overall performance of serotoninergic neuromediators system. Its functional condition can be reflected on some aspects of intellectual activity of the person.
METHODS: The level of intellectual development (IQ) is certain at 250 unrelated individuals in the age of 18-35 years by nonverbal Kettel test.
According to parameters IQ examinees are divided into three groups: with a normal level of intellectual development (IQ within the limits of 90-110 points), high (above 110 points) and low (below 90 points). The analysis of genetic polymorphism 5-HTTLPR is carried out by a method PCR. RESULTS: Genotypes 1)*L/*L, 2)*L/*S, 3)*S/*S met frequency 1) 28%, 2) 42%, 3) 30% in group of comparison, 1) 21.4%, 2) 59.5%, 3) 19.1% in group with high parameters IQ and 1) 33.3%, 2) 41.67%, 3) 25% in group with low level IQ. The analysis of associations has shown statistically significant distinctions in distribution of frequencies genotypes of gene SLC6A4 between group of comparison and group with high parameters IQ (c2=8.313; P=0.017), owing to increase of frequency of genotype SLC6A4*L/*S (59.5 % against 42 % in group of comparison; P=0.030; OR=1.418; 95%CI 1.069-1.836) in group of persons with high parameters IQ.
Is known, that the presence in genotype of allele SLC6A4*L provides high level expression of serotonin transporter gene and the high intensity of metabolism of serotonin, that is accelerating the process of pulse transmission through carrying intensification of serotonin from synaptic trough in presinaps.
Reelin gene variation in working memory performance
J. Wedenoja1, A. Tuulio-Henriksson2,3, J. Suvisaari2, T. Paunio1,4, A. Loukola1, J. Ekelund1,4, T. Varilo1, T. Partonen2, J. Lönnqvist2,4, L. Peltonen1,5;
1Institute for Molecular Medicine Finland FIMM, National Public Health Institute, Helsinki, Finland, 2Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 3Department of Psychology, University of Helsinki, Helsinki, Finland, 4Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland, 5Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Presentation Number: P06.251
Lack of convincing results in gene identification for psychiatric disorders has increased interest towards quantitative traits and endophenotypes, which provide more power for the data analysis and are potentially more closely related to underlying biology.
In our previous study, we replicated schizophrenia linkage on chromosome 7q21-32 in 352 Finnish families. A regional Reelin (RELN) gene on 7q22, encoding for Reelin glycoprotein involved in neuronal migration during the brain development, and contributing to synapse remodelling, crucial for cognitive abilities, showed strong association with with an intragenic microsatellite marker (STR) and multiple cognitive traits in a subsample of 186 families with 618 neuropsychologically tested individuals.
Here, we utilized neuropsychological test data from 292 Finnish schizophrenia families with 923 tested individuals and 376 independent Finnish controls, and genotyped 96 RELN intragenic and flanking SNPs, two intragenic STRs, and one STR in RELN promoter. In the family sample, multiple SNPs associated with visual attention, visual working memory, learning, and executive functioning (p=0.006 to 0.0001). Furthermore, we obtained strengthened evidence for association between the previous STR and especially verbal and visual working memory (p=0.007 to 0.00002). Also multiple SNPs associated with positive symptoms of schizophrenia (p=0.005). Interestingly, also in the control sample multiple SNPs associated with visual attention, visual working memory, information processing speed, and general abilities (p=0.004 to 0.00008). The strongest signals emerged from the haploblock harboring the trait-associated STR.
These data provide further evidence for involvement of RELN gene variations in cognitive functions.
A genome-wide association study in schizophrenia using DNA pooling on 574 parent-offspring trios
G. Kirov1, I. Zaharieva1, L. Georgieva1, V. Moskvina1, I. Nikolov1, M. Owen1, M. O'Donovan1, S. Cichon2, A. Hillmer2, D. Toncheva3;
1Cardiff University, Cardiff, United Kingdom, 2University of Bonn, Bonn, Germany, 3University Hospital “Maichin Dom”, Sofia, Bulgaria.
Presentation Number: P06.085
We conducted a genomewide association study (GWAS) on schizophrenia with DNA pooling in order to reduce the cost of the project. We used a parent-offspring trios design in order to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridised each pool 8 times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected for individual genotyping the highest-ranked SNPs, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test (TDT). 40 of those were significant at p<0.05, with the best result at p=1.2x10-6 for rs11064768. This SNP is within the gene CCDC60, a coiled-coil domain gene. The most interesting result was for the third-best SNP: rs893703 (p = 0.00016), within RBP1, a candidate gene for schizophrenia.
Neuropeptide Y gene variation and association with alcohol consumption in a Spanish Mediterranean population
F. Frances, J. V. Sorli, O. Portolés, P. Guillem-Sáiz, J. I. González, D. Corella;
Preventive Medicine Dept. and CIBER obn, Valencia, Spain.
Presentation Number: P07.095
Background and objective: Neuropeptide Y (NPY) is a neurotransmitter widely distributed in the central nervous system. Both intraamygdalar injection and overexpression experiments in animals have demonstrated that increases of NPY in the amygdala reduces alcohol intake and anxiety manifestations in anxious rats. In humans, some studies have associated the Leu7Pro polymorphism in the NPY with alcohol consumption, but the evidence is scarce. In the Spanish Mediterranean population, the Leu7Pro variant is not polymorphic. Thus, our aim was to identify novel exonic variants in the NPY as well as the study previously described intronic variants, and their association with alcohol consumption in this population.
Methods: 911 subjects (321 men and 590 women) from the Spanish Mediterranean population were recruited. Alcohol consumption and demographic and lifestyle variables were measured. Nucleotide sequence determination and SNP analyses were carried out.
Results: Only one exonic SNP was detected by direct sequencing (1258G>A or rs9785023; allele frequency 0.47). From the intronic markers chosen (483A>G or rs13235938, 2517A>G or rs4722342 and 7065A>G or rs 4722343), only the last ones were polymorphic (allele frequencies 0.46 and 0.40 respectively), and none of them were associated with alcohol consumption. However, the 1258G>A SNP was associated (recessive pattern) with higher alcohol intake in drinkers. This association was particularly relevant in men with a moderate intake (40±9 g/d in GG, 41±8 g/d in GA and 59±5 g/day in AA; p<0.05).
Conclusions: The 1258G>A in the NPY is associated with alcohol consumption in the Mediterranean population.
Recent adaptive selection at MAOB and ancestral susceptibility to schizophrenia
N. Carrera1, J. Sanjuán2, M. Moltó3, Á. Carracedo1,4, J. Costas1;
1Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain, 2Psychiatric Unit, Faculty of Medicine, Clinical Hospital, University of Valencia, Valencia, Spain, 3Department of Genetics, Faculty of Biology, University of Valencia, Valencia, Spain, 4Genomic Medicine Group, Institute of Legal Medicine, University of Santiago de Compostela, and CIBERER, Santiago de Compostela, Spain.
Presentation Number: P06.263
The ancestral susceptibility hypothesis has been proposed to explain the existence of common susceptibility alleles. Some ancestral alleles, reflecting ancient adaptations, may be poorly adapted to the more contemporary environmental conditions giving rise to an increased risk to suffer some common disorders. In order to test this hypothesis in schizophrenia, we focus on monoamine oxidase B (MAOB). This gene is involved in deamination of several monoamines, including both xenobiotic amines present in several foods, as well as neurotransmitters such as dopamine. In addition, preliminary analysis based on phase I HapMap data suggested that recent natural selection have acted on this locus. We further explored the existence of this recent positive selection using a test based on extension of linkage disequilibrium (LD) to large distance at the specific selected haplotype taking data from HapMap phase II, and searched for association of the ancestral haplotypes to schizophrenia in a sample of 532 schizophrenic patients and 597 controls from Spain. Our analysis suggests the existence of a haplotype of MAOB subject to recent selection. In agreement with the ancestral susceptibility hypothesis, the ancestral haplotypes were significantly over-represented in patients (P = 0.047). These haplotypes confer an increased risk to schizophrenia, restricted to males (P = 0.024, OR = 1.41, 95% CI 1.01-1.90). Thus, pending on replication studies, MAOB seems to fit the ancestral susceptibility model, opening a new strategy to search for common schizophrenia susceptibility genes by focusing in those functional candidate genes subject to recent positive selection.
Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: evidence of association of BAIAP2 and NEUROD6 with adulthood attention-deficit hyperactivity disorder
M. Ribases1,2, R. Bosch1, A. Hervás3, J. Ramos-Quiroga1,4, A. Bielsa1, X. Gastaminza1, M. Fernández-Anguiano3, M. Nogueira1, N. Gómez-Barros1, X. Estivill5,6, M. Casas1,4, M. Bayés5,6, B. Cormand7,8;
1Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 2Research Group in Childhood Neurology and Psychiatric Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain, 3Child and Adolescent Mental Health Unit, Hospital Mútua de Terrassa, Barcelona, Spain, 4Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 5Genes and Disease Program, Center for Genomic Regulation (CRG), UPF, Barcelona, Spain, 6CIBER Epidemiología y Salud Pública, Instituto de Salud Carlos III (CRG), Barcelona, Spain, 7Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, 8CIBER Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
Presentation Number: P06.005
Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset neuropsychiatric disorder that persists throughout lifespan in at least 30% of ADHD children. Different lines of evidence suggest that abnormal right-left brain asymmetries in ADHD patients may be involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Although the exact mechanisms underlying cerebral lateralization are unknown, left-right cortical asymmetry in humans has been associated with transcriptional asymmetry at early embryonic stages and a number of genes differentially expressed between hemispheres have been identified. Among these, we selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, ID2) and performed a case-control analysis in 531 ADHD patients (320 children and 211 adults) and 531 sex-matched unrelated controls. The single- and multiple-marker analysis provided preliminary evidence for the contribution of BAIAP2 (P=8.5e-06; OR = 2.69 (1.74-4.17)) and NEUROD6 (P = 0.0053, OR = 1.76 (1.18-2.61)) to adulthood ADHD. Additionally, association between both genes and performance deficits in the Conners Continuous Performance Test (CPT-II) was also identified. Our results support the participation of BAIAP2 and NEUROD6 in the continuity of ADHD across lifespan and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in the predisposition to this neurodevelopmental disorder.
Associations between serotonin transporter gene SLC6A4 polymorphism and level of intellectual development (IQ) of the person
O. Gumerova, E. V. Lekontsev, V. Y. Gorbunova;
Bashkir State Pedagogical University it. M. Akmulla, Ufa, Russian Federation.
Presentation Number: P07.100
INTRODUCTION: Serotonin transporter gene SLC6A4 (17q11.1-12) is one of the basic genes, which define an overall performance of serotoninergic neuromediators system. Its functional condition can be reflected on some aspects of intellectual activity of the person.
METHODS: The level of intellectual development (IQ) is certain at 250 unrelated individuals in the age of 18-35 years by nonverbal Kettel test.
According to parameters IQ examinees are divided into three groups: with a normal level of intellectual development (IQ within the limits of 90-110 points), high (above 110 points) and low (below 90 points). The analysis of genetic polymorphism 5-HTTLPR is carried out by a method PCR. RESULTS: Genotypes 1)*L/*L, 2)*L/*S, 3)*S/*S met frequency 1) 28%, 2) 42%, 3) 30% in group of comparison, 1) 21.4%, 2) 59.5%, 3) 19.1% in group with high parameters IQ and 1) 33.3%, 2) 41.67%, 3) 25% in group with low level IQ. The analysis of associations has shown statistically significant distinctions in distribution of frequencies genotypes of gene SLC6A4 between group of comparison and group with high parameters IQ (c2=8.313; P=0.017), owing to increase of frequency of genotype SLC6A4*L/*S (59.5 % against 42 % in group of comparison; P=0.030; OR=1.418; 95%CI 1.069-1.836) in group of persons with high parameters IQ.
Is known, that the presence in genotype of allele SLC6A4*L provides high level expression of serotonin transporter gene and the high intensity of metabolism of serotonin, that is accelerating the process of pulse transmission through carrying intensification of serotonin from synaptic trough in presinaps.
Reelin gene variation in working memory performance
J. Wedenoja1, A. Tuulio-Henriksson2,3, J. Suvisaari2, T. Paunio1,4, A. Loukola1, J. Ekelund1,4, T. Varilo1, T. Partonen2, J. Lönnqvist2,4, L. Peltonen1,5;
1Institute for Molecular Medicine Finland FIMM, National Public Health Institute, Helsinki, Finland, 2Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 3Department of Psychology, University of Helsinki, Helsinki, Finland, 4Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland, 5Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Presentation Number: P06.251
Lack of convincing results in gene identification for psychiatric disorders has increased interest towards quantitative traits and endophenotypes, which provide more power for the data analysis and are potentially more closely related to underlying biology.
In our previous study, we replicated schizophrenia linkage on chromosome 7q21-32 in 352 Finnish families. A regional Reelin (RELN) gene on 7q22, encoding for Reelin glycoprotein involved in neuronal migration during the brain development, and contributing to synapse remodelling, crucial for cognitive abilities, showed strong association with with an intragenic microsatellite marker (STR) and multiple cognitive traits in a subsample of 186 families with 618 neuropsychologically tested individuals.
Here, we utilized neuropsychological test data from 292 Finnish schizophrenia families with 923 tested individuals and 376 independent Finnish controls, and genotyped 96 RELN intragenic and flanking SNPs, two intragenic STRs, and one STR in RELN promoter. In the family sample, multiple SNPs associated with visual attention, visual working memory, learning, and executive functioning (p=0.006 to 0.0001). Furthermore, we obtained strengthened evidence for association between the previous STR and especially verbal and visual working memory (p=0.007 to 0.00002). Also multiple SNPs associated with positive symptoms of schizophrenia (p=0.005). Interestingly, also in the control sample multiple SNPs associated with visual attention, visual working memory, information processing speed, and general abilities (p=0.004 to 0.00008). The strongest signals emerged from the haploblock harboring the trait-associated STR.
These data provide further evidence for involvement of RELN gene variations in cognitive functions.
A genome-wide association study in schizophrenia using DNA pooling on 574 parent-offspring trios
G. Kirov1, I. Zaharieva1, L. Georgieva1, V. Moskvina1, I. Nikolov1, M. Owen1, M. O'Donovan1, S. Cichon2, A. Hillmer2, D. Toncheva3;
1Cardiff University, Cardiff, United Kingdom, 2University of Bonn, Bonn, Germany, 3University Hospital “Maichin Dom”, Sofia, Bulgaria.
Presentation Number: P06.085
We conducted a genomewide association study (GWAS) on schizophrenia with DNA pooling in order to reduce the cost of the project. We used a parent-offspring trios design in order to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridised each pool 8 times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected for individual genotyping the highest-ranked SNPs, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test (TDT). 40 of those were significant at p<0.05, with the best result at p=1.2x10-6 for rs11064768. This SNP is within the gene CCDC60, a coiled-coil domain gene. The most interesting result was for the third-best SNP: rs893703 (p = 0.00016), within RBP1, a candidate gene for schizophrenia.
Neuropeptide Y gene variation and association with alcohol consumption in a Spanish Mediterranean population
F. Frances, J. V. Sorli, O. Portolés, P. Guillem-Sáiz, J. I. González, D. Corella;
Preventive Medicine Dept. and CIBER obn, Valencia, Spain.
Presentation Number: P07.095
Background and objective: Neuropeptide Y (NPY) is a neurotransmitter widely distributed in the central nervous system. Both intraamygdalar injection and overexpression experiments in animals have demonstrated that increases of NPY in the amygdala reduces alcohol intake and anxiety manifestations in anxious rats. In humans, some studies have associated the Leu7Pro polymorphism in the NPY with alcohol consumption, but the evidence is scarce. In the Spanish Mediterranean population, the Leu7Pro variant is not polymorphic. Thus, our aim was to identify novel exonic variants in the NPY as well as the study previously described intronic variants, and their association with alcohol consumption in this population.
Methods: 911 subjects (321 men and 590 women) from the Spanish Mediterranean population were recruited. Alcohol consumption and demographic and lifestyle variables were measured. Nucleotide sequence determination and SNP analyses were carried out.
Results: Only one exonic SNP was detected by direct sequencing (1258G>A or rs9785023; allele frequency 0.47). From the intronic markers chosen (483A>G or rs13235938, 2517A>G or rs4722342 and 7065A>G or rs 4722343), only the last ones were polymorphic (allele frequencies 0.46 and 0.40 respectively), and none of them were associated with alcohol consumption. However, the 1258G>A SNP was associated (recessive pattern) with higher alcohol intake in drinkers. This association was particularly relevant in men with a moderate intake (40±9 g/d in GG, 41±8 g/d in GA and 59±5 g/day in AA; p<0.05).
Conclusions: The 1258G>A in the NPY is associated with alcohol consumption in the Mediterranean population.
Recent adaptive selection at MAOB and ancestral susceptibility to schizophrenia
N. Carrera1, J. Sanjuán2, M. Moltó3, Á. Carracedo1,4, J. Costas1;
1Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain, 2Psychiatric Unit, Faculty of Medicine, Clinical Hospital, University of Valencia, Valencia, Spain, 3Department of Genetics, Faculty of Biology, University of Valencia, Valencia, Spain, 4Genomic Medicine Group, Institute of Legal Medicine, University of Santiago de Compostela, and CIBERER, Santiago de Compostela, Spain.
Presentation Number: P06.263
The ancestral susceptibility hypothesis has been proposed to explain the existence of common susceptibility alleles. Some ancestral alleles, reflecting ancient adaptations, may be poorly adapted to the more contemporary environmental conditions giving rise to an increased risk to suffer some common disorders. In order to test this hypothesis in schizophrenia, we focus on monoamine oxidase B (MAOB). This gene is involved in deamination of several monoamines, including both xenobiotic amines present in several foods, as well as neurotransmitters such as dopamine. In addition, preliminary analysis based on phase I HapMap data suggested that recent natural selection have acted on this locus. We further explored the existence of this recent positive selection using a test based on extension of linkage disequilibrium (LD) to large distance at the specific selected haplotype taking data from HapMap phase II, and searched for association of the ancestral haplotypes to schizophrenia in a sample of 532 schizophrenic patients and 597 controls from Spain. Our analysis suggests the existence of a haplotype of MAOB subject to recent selection. In agreement with the ancestral susceptibility hypothesis, the ancestral haplotypes were significantly over-represented in patients (P = 0.047). These haplotypes confer an increased risk to schizophrenia, restricted to males (P = 0.024, OR = 1.41, 95% CI 1.01-1.90). Thus, pending on replication studies, MAOB seems to fit the ancestral susceptibility model, opening a new strategy to search for common schizophrenia susceptibility genes by focusing in those functional candidate genes subject to recent positive selection.
Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: evidence of association of BAIAP2 and NEUROD6 with adulthood attention-deficit hyperactivity disorder
M. Ribases1,2, R. Bosch1, A. Hervás3, J. Ramos-Quiroga1,4, A. Bielsa1, X. Gastaminza1, M. Fernández-Anguiano3, M. Nogueira1, N. Gómez-Barros1, X. Estivill5,6, M. Casas1,4, M. Bayés5,6, B. Cormand7,8;
1Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 2Research Group in Childhood Neurology and Psychiatric Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain, 3Child and Adolescent Mental Health Unit, Hospital Mútua de Terrassa, Barcelona, Spain, 4Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 5Genes and Disease Program, Center for Genomic Regulation (CRG), UPF, Barcelona, Spain, 6CIBER Epidemiología y Salud Pública, Instituto de Salud Carlos III (CRG), Barcelona, Spain, 7Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, 8CIBER Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
Presentation Number: P06.005
Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset neuropsychiatric disorder that persists throughout lifespan in at least 30% of ADHD children. Different lines of evidence suggest that abnormal right-left brain asymmetries in ADHD patients may be involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Although the exact mechanisms underlying cerebral lateralization are unknown, left-right cortical asymmetry in humans has been associated with transcriptional asymmetry at early embryonic stages and a number of genes differentially expressed between hemispheres have been identified. Among these, we selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, ID2) and performed a case-control analysis in 531 ADHD patients (320 children and 211 adults) and 531 sex-matched unrelated controls. The single- and multiple-marker analysis provided preliminary evidence for the contribution of BAIAP2 (P=8.5e-06; OR = 2.69 (1.74-4.17)) and NEUROD6 (P = 0.0053, OR = 1.76 (1.18-2.61)) to adulthood ADHD. Additionally, association between both genes and performance deficits in the Conners Continuous Performance Test (CPT-II) was also identified. Our results support the participation of BAIAP2 and NEUROD6 in the continuity of ADHD across lifespan and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in the predisposition to this neurodevelopmental disorder.
Athletic ability (ESHG 2008 abstracts)
European Human Genetics Conference (abstract database)
The ACE I/D polymorphism in Lithuanian professional athletes
V. Ginevic(iene.1,2, J. Kasnauskiene.1, V. Kuc(inskas1;
1Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania, 2Lithuanian Olympic Sports Centre, Vilnius, Lithuania.
Presentation Number: P07.002
Human physical performance is under strong influence of genetic factors. I/D polymorphism in the human angiotensin-1-coverting enzyme (ACE) gene characterised by the presence (I allele) or absence (D allele) of a 287-base-pair Alu repeat within intron 16 is among most extensively investigated ones with respect to ACE activity and its involvement in various pathophysiological conditions related to endurance. Nevertheless, the results are still conflicting across studies and populations. In the present study, ACE gene I/D polymorphism was investigated in 413 Lithuanian professional athletes representing four functional groups [endurance (N=57); mixed sports (N=44); strength and speed (N=30), and team sports (N=282)], as well as in 120 samples from general population of Lithuanians. Statistically significantly higher D allele frequencies were found in strength and speed group (P=0.02) as well as in endurance group (P=0.06), contrary to the prevailing data from other studies showing association of endurance with I allele. D allele also appeared to be more frequent in the general population of Lithuanians (60,4 %) in comparison to the majority of other European populations (30-50%). Thus, increased D allele prevalence in strength and speed group of athletes from Lithuania can be a reflection of population frequency of this allele. In conclusion, our results imply that the role of ACE gene I/D polymorphism in athletic performance is not straightforward and can be masked by other genetic and non-genetic factors.
Association of the ACTN3 gene variant with endurance athlete status
A. M. Druzhevskaya, I. I. Ahmetov, I. V. Astratenkova, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P07.003
Alpha-actinin-3 (ACTN3) is a myofibrillar protein found in fast-twitch glycolytic muscle fibers. The less common X-allele of the R577X polymorphism in the ACTN3 gene results in a premature stop codon and alpha-actinin-3 protein deficiency in XX homozygotes. A strong association has been reported between the R577X polymorphism and elite athletic performance. The aim of the study was to investigate genotype and allele distribution of ACTN3 gene in endurance-oriented athletes and controls. The study involved 501 athletes (biathletes; rowers; long distance runners, swimmers and skaters, road cyclists, skiers, triathletes, race walkers) and 1197 controls. Genotyping was performed by restriction fragment length polymorphism analysis. The distribution of ACTN3 genotypes (athletes: RR - 37.1%, RX - 53.1%, XX - 9.8%; controls: RR - 36.8%, RX - 49.0%, XX - 14.2%) was significantly different between athletes and controls (P=0.038). While R allele frequency did not differ between athletes (63.7%) and controls (61.3%), the frequency of XX genotype was under-represented in athletes compared to controls (9.8% vs. 14.2%, P=0.013). We therefore conclude that XX genotype is unfavorable for endurance performance.
HIF1A gene polymorphism is associated with power performance in athletes
A. M. Hakimullina, I. I. Ahmetov, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.129
Glycolysis is the central source of anaerobic energy in humans, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1a (HIF-1a). HIF-1a controls a number of genes that are implicated in various cellular functions including cell proliferation (erythropoietin), glucose metabolism (glucose transporters and glycolytic enzymes), cell survival, and angiogenesis (vascular endothelial growth factor and VEGF receptors). A missense polymorphism, Pro582Ser, is present in exon 12 (C/T at bp 85). The rare T-allele is predicted to result in a proline to serine change in the amino acid sequence of the protein. This substitution increases protein stability and transcriptional activity, and therefore, improves glucose metabolism and angiogenesis. In this study, we investigated whether genetic variation at the locus encoding HIF1A is associated with elite athlete status in weightlifters, for which glycolysis is crucial for power performance. The study involved 53 Russian athletes (17 sub-elite, 32 elite and 4 highly elite) and 920 controls. HIF1A gene Pro582Ser polymorphism was determined by PCR-RLFP. The frequency of the rare Ser allele was significantly higher in weightlifters than in controls (17.9% vs. 8.5%; P=0.001). Moreover, the frequency of Ser allele increased with growing skill level of athletes (sub-elite (14.7%) - elite (18.8%) - highly elite (25.0%)). Thus, HIF1A gene Pro582Ser polymorphism is associated with elite power athlete status, which suggests an important role for HIF-1a in skeletal muscle adaptation to power training.
The ability to become an elite endurance athlete depends on the carriage of high number of endurance-related alleles
I. I. Ahmetov, A. M. Hakimullina, J. V. Shikhova, I. A. Mozhayskaya, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.233
The objective was to evaluate the total contribution of CNB, NFATC4, PGC1A, PGC1B, TFAM, VEGF, UCP2, UCP3 gene alleles in defining predisposition to sports. The study involved 1580 Russian athletes and 1057 controls. CNB (calcineurin B) 5I/5D, NFATC4 (nuclear factor of activated T-cells, calcineurin-dependent 4) Ala160Gly, PGC1A (PPARgamma coactivator-1-alpha) Gly482Ser, PGC1B (PPARgamma coactivator-1-beta) Ala203Pro, TFAM (transcription factor A, mitochondrial) Thr12Ser, VEGF (vascular endothelial growth factor) G-634C, UCP2 (uncoupling protein 2) Ala55Val, UCP3 (uncoupling protein 3) -55C/T gene polymorphisms were determined by PCR-RLFP. We found that the frequency of endurance-related alleles (CNB I, NFATC4 Gly, PGC1A Gly, PGC1B Pro, TFAM Thr, VEGF C, UCP2 Val, UCP3 T) were significantly higher in Russian elite endurance-oriented athletes (n=351) compared to controls, both separately and cumulatively (45.6% vs. 37.4%, p<0.0001). Furthermore, 66.7% of highly elite endurance-oriented athletes (Olympic and World championship winners; n=12) were carriers of 8 to 12 endurance-related alleles (the others were carriers of 7 alleles), while there were only 18.1% of such persons in the control group (p<0.0001). Thus, the success in sports can be attributed to the carriage of high number of alleles associated with certain physical qualities.
NFATC4 gene polymorphism and aerobic performance in athletes
D. V. Popov1, I. I. Ahmetov2, J. V. Shikhova2, S. S. Missina1, O. L. Vinogradova1, V. A. Rogozkin2;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci., Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.209
Nuclear factor of activated T cells C4 gene (NFATC4) encodes transcription factor which regulates cardiac and skeletal muscle metabolism. The aim of the study was to investigate allelic distribution of NFATC4 gene Gly160Ala polymorphism in endurance-oriented athletes (n=549) and controls (n=1057), and to find interrelation between genotypes and physiological parameters in rowers (n=90). Genotyping was performed by restriction fragment length polymorphism analysis. Physiological parameters were evaluated by PM 3 Rower Ergometer and MetaMax 3B Gas Analyzer. The frequency of NFATC4 Gly allele was significantly higher in athletes than in controls (51.5% vs. 43.7%; p<0.0001), and increased with the growth of skills (sub-elite athletes: 36.7%-48.5%; highly elite athletes: 60.6%-62.5%). Furthermore, NFATC4 Gly allele was associated with high values of aerobic performance (when VO2max and AT in % of VO2max were measured). Thus, NFATC4 gene Gly160Ala polymorphism is associated with aerobic performance of athletes and plays an important role in sports selection.
VEGF A2578C polymorphism is associated with muscle fiber type distribution in athletes
E. V. Lyubaeva1, I. I. Ahmetov2, A. M. Hakimullina2, O. L. Vinogradova1, V. A. Rogozkin2;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci., Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.309
There is strong relationship between muscle fiber type distribution and human physical performance. For example, elite weightlifters and sprinters exhibit large percentages of fast-twitch fibers (FT, also known as type II muscle fibers) compared to controls and endurance athletes. FT fibers have comparatively low capillary density and blood flow capacity and low mitochondria content. Vascular endothelial growth factor (VEGF) is important in the basal maintenance of skeletal muscle capillarization and may influence the determination of muscle fiber type distribution. To investigate the question of the influence of VEGF gene polymorphism on the proportion of fibers types of m. vastus lateralis, we have analyzed the muscle biopsies obtained from 21 elite Russian athletes (all-round speed skaters). The immunoperoxidase technique was employed for immunohistochemical identification of myosin isoforms. VEGF gene A2578C polymorphism was determined by PCR-RLFP. Mean percentages of FT fibers were significantly higher in VEGF CC homozygotes than in VEGF A allele carriers (AA/AC - 38.3 (6.2) %, CC - 47.8 (12.4) %; P=0.03). Then we determined distribution of VEGF alleles in 60 elite and sub-elite weightlifters and in 1,113 controls. We found that the frequency of VEGF 2578C allele was significantly higher in weightlifters than in controls (58.3% vs. 48.0%; P=0.035). In conclusion, VEGF 2578C allele is associated with increased proportion of FT muscle fibers in all-round speed skaters and with elite power athlete status.
UCP3 gene polymorphism and cardiac growth in response to 1 year of endurance training
S. B. Goriyeva1, I. I. Ahmetov1,2, O. L. Vinogradova1;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci, Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.300
Reduced fatty acid utilization and increased oxidative stress both can contribute to the development of cardiac hypertrophy. Left ventricular hypertrophy in endurance-oriented athletes is generally understood to be a limiting factor for improving maximal oxygen uptake (VO2max). Cardiac uncoupling protein 3 (UCP3) can serve to protect the heart against lipid-induced oxidative stress, and stimulate fatty acid transport and oxidation. A variant in the UCP3 gene associated with higher mRNA levels has been identified (UCP3 -55C/T). This variant has been associated with reduced risk of type 2 diabetes and obesity. Recently we have shown that -55T allele was overrepresented in highly elite rowers and was associated with high values of VO2max. If UCP3 is important for muscle and heart metabolism and can protect against development of LVH, then one might anticipate -55T variant of UCP3 gene to be associated with insignificant cardiac growth (rational adaptation) in response to endurance training. We have tested this hypothesis in the study of elite Russian rowers (n=19, males). UCP3 -55C/T polymorphism was determined by PCR-RLFP. Echocardiography was performed for two times with one year interval. We found that subjects of CC genotype exhibited the greatest cardiac growth (when interventricular septal wall thickness was measured; CC: 3 (1.4) mm, CT: 1 (0) mm, TT: -1 mm; P=0.019), whereas the individuals of TT genotype exhibited the reduction in septal wall thickness. In conclusion, we demonstrate that variation in the UCP3 gene influences cardiac growth in response to endurance training in rowers.
The interaction between gene polymorphisms and carbohydrate intake on metabolic profile in Russian athletes
A. A. Topanova, I. I. Ahmetov, R. R. Dondukovskaya, N. D. Golberg;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.212
Genetic and nutritional factors interact together and modulate the plasma carbohydrate and lipid profile. The objective was to study whether carbohydrate intake modulates the association between NFATC4, PGC1A, PPARA, PPARG, PPARD, TFAM, UCP2 and UCP3 gene variations and metabolic profile in Russian athletes. The study involved 33 male Russian sub-elite endurance-oriented athletes (road cyclists), who were randomly assigned to consume carbohydrates/minerals (CARB, n=17; 6% 200 ml drink “Olympia” (Estonia)) or placebo (CON, n=16; 200 ml pure water) for 20 d at 20th min from the end of evening training. Plasma concentrations of total cholesterol, glucose and resting lactate (La) were evaluated in the morning before and at the end of experiment. NFATC4 Ala160Gly, PGC1A Gly482Ser, PPARA G/C, PPARG Pro12Ala, PPARD +294T/C, TFAM Thr12Ser, UCP2 Ala55Val, UCP3 -55C/T gene polymorphisms were determined by PCR-RLFP. At base-line PPARA C allele carriers exhibited the highest values of La (P=0.008); NFATC4 Ala (P=0.04) and TFAM Ser (P=0.024) alleles were associated with higher glucose concentrations. At the end of experiment PGC1A Ser (r=0.54, P=0.03), PPARG Pro (r=0.58, P=0.019) alleles were positively correlated with high values of La in CARB- and CON-groups, respectively, whilst PPARD C allele (r=0.47, P=0.055) was associated with higher total cholesterol levels in CARB-group. Furthermore, PPARG Pro allele carriers of CARB-group showed the greatest decrease in total cholesterol. Thus, polymorphisms of PGC1A, PPARG and PPARD genes (involved in carbohydrate and lipid metabolism) may interact with carbohydrate intake to modulate metabolic profile of endurance-oriented athletes.
Polymorphisms in ACTN3, ACE and AMPD1 genes and physical performance in Bulgarian sub-elite athletes
S. A. Andonov1, R. Saraeva2, S. Andonova2,3, R. Kaneva2,3, V. Gigova1, L. Stefanov1, I. Kremensky2,3, P. Atanasov1;
1National Sports Academy “Vassil Levski”, Sofia, Bulgaria, 2Molecular Medicine Center, Medical University, Sofia, Bulgaria, 3University Hospital of Obstetrics, Sofia, Bulgaria.
Presentation Number: P06.004
The aim of this study was to analyse ACTN3 (R577X), ACE (I/D) and AMPD1 (34C>T) polymorphisms in sub-elite athletes (n=70, 57 males and 13 females) and controls (n=44, 15 males and 29 females). The correlations between genotypes and physiological and biochemical parameters at anaerobic conditions was investigated. Athletes were divided into three sport groups according to a power-time model of performance intensity. The physiological parameters were evaluated by standard Wingate Anaerobic Test and Ergospirometry. Spectrophotometry and Blood-Gas analysis were used for the estimation of the glycolytic enzyme activity of Lactate Dehydrogenase and Acid-Base Balance, respectively. DNA samples was genotyped by RFLP analysis followed by agarose gel-electrophoresis. Differences in the distribution of alleles and genotypes between the groups were assessed by x2-test. Statistical analysis of variances was performed using one way ANOVA. No significant differences between the athletes and controls was found according the allele and genotype frequencies of the investigated polymorphisms. AMPD1 heterozygous male athletes in the “Anaerobic” group showed greater Mean Power Output (Watts) in comparison to CC homozygous athletes (9,11 vs. 7,34 Watts). Significant correlation was observed also with the buffering capacity (HCO3 and BE). No Individuals homozygous for the T-allele of AMPD1 were found. The ACTN3 genotype correlated with parameters relevant to exercise capacity such as oxygen uptake, saturation and Lean Body Mass in the male sub-groups of anaerobic sports and endurance sports, but not in the female sub-groups.
Skeletal Muscle Gene ACTN3 and Physical Performance:
O. Kas?may1, D. Sevinc2, S. O. Iseri1, K. Ulucan3, M. Unal1, A. I. Guney4, H. Kurtel1;
1Marmara University, School of Medicine, Sport Physiology Department, Istanbul, Turkey, 2Maltepe University, School of Medicine, Medical Biology and Genetics Department, Istanbul, Turkey, 3Marmara University, School of Dentistry, Medical Biology and Genetics Department, Istanbul, Turkey, 4Marmara University, School of Medicine, Medical Genetics Department, Istanbul, Turkey.
Presentation Number: P07.046
ACTN3 gene is responsible from the production of alpha-actinin-3 protein, which has force-generating capacity of muscle fibers, and which is restricted to fast fibers. Homozygosity for 577X in ACTN3 (R577XX) results in no production of a-actinin-3 protein. Recent studies show that elite sprint athletes had a higher frequency of the RR genotype. Aim: The purpose of the study was to investigate ACTN3 gene variations and their probable phenotypic reflection by using physiological methods, and to show ACTN3 polymorphism in Turkish soccer players (n=31). Methods: After determining the genotypes by analyzing the blood samples, three groups (XX,RR,RX) were formed. The groups were existing R577X variant in both ACTN3 genes (XX,n=4), not existing R577X variant in both ACTN3 genes (RR,n=22), or existing R577X variant only one of the two ACTN3 genes (RX,n=5), respectively. To determine aerobic performance, Bruce protocol was applied on treadmill and maximal oxygen consumption (VO2max) was measured by metabolic analyzer. On a separate day, anaerobic performance was evaluated by Wingate test. Student’s t-test or analysis of variance (ANOVA) was used for comparisons. Results: Thirteen % of the soccer players had homozygosity for R577XX codon. The VO2max levels in XX group tended to be higher from RR (p=0.09) and RX groups (p=0.05). VO2/HR (pulse oxygen) and VEmax (maximum ventilation) levels were not different between groups. Peak power values tended to be higher in RR group from the other groups. Our results evaluated the effect of genotypic variations on sprint and endurance performance of athletes contributing the understanding of genotype-phenotype correlation.
The ACE I/D polymorphism in Lithuanian professional athletes
V. Ginevic(iene.1,2, J. Kasnauskiene.1, V. Kuc(inskas1;
1Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania, 2Lithuanian Olympic Sports Centre, Vilnius, Lithuania.
Presentation Number: P07.002
Human physical performance is under strong influence of genetic factors. I/D polymorphism in the human angiotensin-1-coverting enzyme (ACE) gene characterised by the presence (I allele) or absence (D allele) of a 287-base-pair Alu repeat within intron 16 is among most extensively investigated ones with respect to ACE activity and its involvement in various pathophysiological conditions related to endurance. Nevertheless, the results are still conflicting across studies and populations. In the present study, ACE gene I/D polymorphism was investigated in 413 Lithuanian professional athletes representing four functional groups [endurance (N=57); mixed sports (N=44); strength and speed (N=30), and team sports (N=282)], as well as in 120 samples from general population of Lithuanians. Statistically significantly higher D allele frequencies were found in strength and speed group (P=0.02) as well as in endurance group (P=0.06), contrary to the prevailing data from other studies showing association of endurance with I allele. D allele also appeared to be more frequent in the general population of Lithuanians (60,4 %) in comparison to the majority of other European populations (30-50%). Thus, increased D allele prevalence in strength and speed group of athletes from Lithuania can be a reflection of population frequency of this allele. In conclusion, our results imply that the role of ACE gene I/D polymorphism in athletic performance is not straightforward and can be masked by other genetic and non-genetic factors.
Association of the ACTN3 gene variant with endurance athlete status
A. M. Druzhevskaya, I. I. Ahmetov, I. V. Astratenkova, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P07.003
Alpha-actinin-3 (ACTN3) is a myofibrillar protein found in fast-twitch glycolytic muscle fibers. The less common X-allele of the R577X polymorphism in the ACTN3 gene results in a premature stop codon and alpha-actinin-3 protein deficiency in XX homozygotes. A strong association has been reported between the R577X polymorphism and elite athletic performance. The aim of the study was to investigate genotype and allele distribution of ACTN3 gene in endurance-oriented athletes and controls. The study involved 501 athletes (biathletes; rowers; long distance runners, swimmers and skaters, road cyclists, skiers, triathletes, race walkers) and 1197 controls. Genotyping was performed by restriction fragment length polymorphism analysis. The distribution of ACTN3 genotypes (athletes: RR - 37.1%, RX - 53.1%, XX - 9.8%; controls: RR - 36.8%, RX - 49.0%, XX - 14.2%) was significantly different between athletes and controls (P=0.038). While R allele frequency did not differ between athletes (63.7%) and controls (61.3%), the frequency of XX genotype was under-represented in athletes compared to controls (9.8% vs. 14.2%, P=0.013). We therefore conclude that XX genotype is unfavorable for endurance performance.
HIF1A gene polymorphism is associated with power performance in athletes
A. M. Hakimullina, I. I. Ahmetov, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.129
Glycolysis is the central source of anaerobic energy in humans, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1a (HIF-1a). HIF-1a controls a number of genes that are implicated in various cellular functions including cell proliferation (erythropoietin), glucose metabolism (glucose transporters and glycolytic enzymes), cell survival, and angiogenesis (vascular endothelial growth factor and VEGF receptors). A missense polymorphism, Pro582Ser, is present in exon 12 (C/T at bp 85). The rare T-allele is predicted to result in a proline to serine change in the amino acid sequence of the protein. This substitution increases protein stability and transcriptional activity, and therefore, improves glucose metabolism and angiogenesis. In this study, we investigated whether genetic variation at the locus encoding HIF1A is associated with elite athlete status in weightlifters, for which glycolysis is crucial for power performance. The study involved 53 Russian athletes (17 sub-elite, 32 elite and 4 highly elite) and 920 controls. HIF1A gene Pro582Ser polymorphism was determined by PCR-RLFP. The frequency of the rare Ser allele was significantly higher in weightlifters than in controls (17.9% vs. 8.5%; P=0.001). Moreover, the frequency of Ser allele increased with growing skill level of athletes (sub-elite (14.7%) - elite (18.8%) - highly elite (25.0%)). Thus, HIF1A gene Pro582Ser polymorphism is associated with elite power athlete status, which suggests an important role for HIF-1a in skeletal muscle adaptation to power training.
The ability to become an elite endurance athlete depends on the carriage of high number of endurance-related alleles
I. I. Ahmetov, A. M. Hakimullina, J. V. Shikhova, I. A. Mozhayskaya, V. A. Rogozkin;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.233
The objective was to evaluate the total contribution of CNB, NFATC4, PGC1A, PGC1B, TFAM, VEGF, UCP2, UCP3 gene alleles in defining predisposition to sports. The study involved 1580 Russian athletes and 1057 controls. CNB (calcineurin B) 5I/5D, NFATC4 (nuclear factor of activated T-cells, calcineurin-dependent 4) Ala160Gly, PGC1A (PPARgamma coactivator-1-alpha) Gly482Ser, PGC1B (PPARgamma coactivator-1-beta) Ala203Pro, TFAM (transcription factor A, mitochondrial) Thr12Ser, VEGF (vascular endothelial growth factor) G-634C, UCP2 (uncoupling protein 2) Ala55Val, UCP3 (uncoupling protein 3) -55C/T gene polymorphisms were determined by PCR-RLFP. We found that the frequency of endurance-related alleles (CNB I, NFATC4 Gly, PGC1A Gly, PGC1B Pro, TFAM Thr, VEGF C, UCP2 Val, UCP3 T) were significantly higher in Russian elite endurance-oriented athletes (n=351) compared to controls, both separately and cumulatively (45.6% vs. 37.4%, p<0.0001). Furthermore, 66.7% of highly elite endurance-oriented athletes (Olympic and World championship winners; n=12) were carriers of 8 to 12 endurance-related alleles (the others were carriers of 7 alleles), while there were only 18.1% of such persons in the control group (p<0.0001). Thus, the success in sports can be attributed to the carriage of high number of alleles associated with certain physical qualities.
NFATC4 gene polymorphism and aerobic performance in athletes
D. V. Popov1, I. I. Ahmetov2, J. V. Shikhova2, S. S. Missina1, O. L. Vinogradova1, V. A. Rogozkin2;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci., Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.209
Nuclear factor of activated T cells C4 gene (NFATC4) encodes transcription factor which regulates cardiac and skeletal muscle metabolism. The aim of the study was to investigate allelic distribution of NFATC4 gene Gly160Ala polymorphism in endurance-oriented athletes (n=549) and controls (n=1057), and to find interrelation between genotypes and physiological parameters in rowers (n=90). Genotyping was performed by restriction fragment length polymorphism analysis. Physiological parameters were evaluated by PM 3 Rower Ergometer and MetaMax 3B Gas Analyzer. The frequency of NFATC4 Gly allele was significantly higher in athletes than in controls (51.5% vs. 43.7%; p<0.0001), and increased with the growth of skills (sub-elite athletes: 36.7%-48.5%; highly elite athletes: 60.6%-62.5%). Furthermore, NFATC4 Gly allele was associated with high values of aerobic performance (when VO2max and AT in % of VO2max were measured). Thus, NFATC4 gene Gly160Ala polymorphism is associated with aerobic performance of athletes and plays an important role in sports selection.
VEGF A2578C polymorphism is associated with muscle fiber type distribution in athletes
E. V. Lyubaeva1, I. I. Ahmetov2, A. M. Hakimullina2, O. L. Vinogradova1, V. A. Rogozkin2;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci., Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.309
There is strong relationship between muscle fiber type distribution and human physical performance. For example, elite weightlifters and sprinters exhibit large percentages of fast-twitch fibers (FT, also known as type II muscle fibers) compared to controls and endurance athletes. FT fibers have comparatively low capillary density and blood flow capacity and low mitochondria content. Vascular endothelial growth factor (VEGF) is important in the basal maintenance of skeletal muscle capillarization and may influence the determination of muscle fiber type distribution. To investigate the question of the influence of VEGF gene polymorphism on the proportion of fibers types of m. vastus lateralis, we have analyzed the muscle biopsies obtained from 21 elite Russian athletes (all-round speed skaters). The immunoperoxidase technique was employed for immunohistochemical identification of myosin isoforms. VEGF gene A2578C polymorphism was determined by PCR-RLFP. Mean percentages of FT fibers were significantly higher in VEGF CC homozygotes than in VEGF A allele carriers (AA/AC - 38.3 (6.2) %, CC - 47.8 (12.4) %; P=0.03). Then we determined distribution of VEGF alleles in 60 elite and sub-elite weightlifters and in 1,113 controls. We found that the frequency of VEGF 2578C allele was significantly higher in weightlifters than in controls (58.3% vs. 48.0%; P=0.035). In conclusion, VEGF 2578C allele is associated with increased proportion of FT muscle fibers in all-round speed skaters and with elite power athlete status.
UCP3 gene polymorphism and cardiac growth in response to 1 year of endurance training
S. B. Goriyeva1, I. I. Ahmetov1,2, O. L. Vinogradova1;
1SRC Institute for Biomedical Problems of the Russian Acad. Sci, Moscow, Russian Federation, 2St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.300
Reduced fatty acid utilization and increased oxidative stress both can contribute to the development of cardiac hypertrophy. Left ventricular hypertrophy in endurance-oriented athletes is generally understood to be a limiting factor for improving maximal oxygen uptake (VO2max). Cardiac uncoupling protein 3 (UCP3) can serve to protect the heart against lipid-induced oxidative stress, and stimulate fatty acid transport and oxidation. A variant in the UCP3 gene associated with higher mRNA levels has been identified (UCP3 -55C/T). This variant has been associated with reduced risk of type 2 diabetes and obesity. Recently we have shown that -55T allele was overrepresented in highly elite rowers and was associated with high values of VO2max. If UCP3 is important for muscle and heart metabolism and can protect against development of LVH, then one might anticipate -55T variant of UCP3 gene to be associated with insignificant cardiac growth (rational adaptation) in response to endurance training. We have tested this hypothesis in the study of elite Russian rowers (n=19, males). UCP3 -55C/T polymorphism was determined by PCR-RLFP. Echocardiography was performed for two times with one year interval. We found that subjects of CC genotype exhibited the greatest cardiac growth (when interventricular septal wall thickness was measured; CC: 3 (1.4) mm, CT: 1 (0) mm, TT: -1 mm; P=0.019), whereas the individuals of TT genotype exhibited the reduction in septal wall thickness. In conclusion, we demonstrate that variation in the UCP3 gene influences cardiac growth in response to endurance training in rowers.
The interaction between gene polymorphisms and carbohydrate intake on metabolic profile in Russian athletes
A. A. Topanova, I. I. Ahmetov, R. R. Dondukovskaya, N. D. Golberg;
St Petersburg Research Institute of Physical Culture, St Petersburg, Russian Federation.
Presentation Number: P06.212
Genetic and nutritional factors interact together and modulate the plasma carbohydrate and lipid profile. The objective was to study whether carbohydrate intake modulates the association between NFATC4, PGC1A, PPARA, PPARG, PPARD, TFAM, UCP2 and UCP3 gene variations and metabolic profile in Russian athletes. The study involved 33 male Russian sub-elite endurance-oriented athletes (road cyclists), who were randomly assigned to consume carbohydrates/minerals (CARB, n=17; 6% 200 ml drink “Olympia” (Estonia)) or placebo (CON, n=16; 200 ml pure water) for 20 d at 20th min from the end of evening training. Plasma concentrations of total cholesterol, glucose and resting lactate (La) were evaluated in the morning before and at the end of experiment. NFATC4 Ala160Gly, PGC1A Gly482Ser, PPARA G/C, PPARG Pro12Ala, PPARD +294T/C, TFAM Thr12Ser, UCP2 Ala55Val, UCP3 -55C/T gene polymorphisms were determined by PCR-RLFP. At base-line PPARA C allele carriers exhibited the highest values of La (P=0.008); NFATC4 Ala (P=0.04) and TFAM Ser (P=0.024) alleles were associated with higher glucose concentrations. At the end of experiment PGC1A Ser (r=0.54, P=0.03), PPARG Pro (r=0.58, P=0.019) alleles were positively correlated with high values of La in CARB- and CON-groups, respectively, whilst PPARD C allele (r=0.47, P=0.055) was associated with higher total cholesterol levels in CARB-group. Furthermore, PPARG Pro allele carriers of CARB-group showed the greatest decrease in total cholesterol. Thus, polymorphisms of PGC1A, PPARG and PPARD genes (involved in carbohydrate and lipid metabolism) may interact with carbohydrate intake to modulate metabolic profile of endurance-oriented athletes.
Polymorphisms in ACTN3, ACE and AMPD1 genes and physical performance in Bulgarian sub-elite athletes
S. A. Andonov1, R. Saraeva2, S. Andonova2,3, R. Kaneva2,3, V. Gigova1, L. Stefanov1, I. Kremensky2,3, P. Atanasov1;
1National Sports Academy “Vassil Levski”, Sofia, Bulgaria, 2Molecular Medicine Center, Medical University, Sofia, Bulgaria, 3University Hospital of Obstetrics, Sofia, Bulgaria.
Presentation Number: P06.004
The aim of this study was to analyse ACTN3 (R577X), ACE (I/D) and AMPD1 (34C>T) polymorphisms in sub-elite athletes (n=70, 57 males and 13 females) and controls (n=44, 15 males and 29 females). The correlations between genotypes and physiological and biochemical parameters at anaerobic conditions was investigated. Athletes were divided into three sport groups according to a power-time model of performance intensity. The physiological parameters were evaluated by standard Wingate Anaerobic Test and Ergospirometry. Spectrophotometry and Blood-Gas analysis were used for the estimation of the glycolytic enzyme activity of Lactate Dehydrogenase and Acid-Base Balance, respectively. DNA samples was genotyped by RFLP analysis followed by agarose gel-electrophoresis. Differences in the distribution of alleles and genotypes between the groups were assessed by x2-test. Statistical analysis of variances was performed using one way ANOVA. No significant differences between the athletes and controls was found according the allele and genotype frequencies of the investigated polymorphisms. AMPD1 heterozygous male athletes in the “Anaerobic” group showed greater Mean Power Output (Watts) in comparison to CC homozygous athletes (9,11 vs. 7,34 Watts). Significant correlation was observed also with the buffering capacity (HCO3 and BE). No Individuals homozygous for the T-allele of AMPD1 were found. The ACTN3 genotype correlated with parameters relevant to exercise capacity such as oxygen uptake, saturation and Lean Body Mass in the male sub-groups of anaerobic sports and endurance sports, but not in the female sub-groups.
Skeletal Muscle Gene ACTN3 and Physical Performance:
O. Kas?may1, D. Sevinc2, S. O. Iseri1, K. Ulucan3, M. Unal1, A. I. Guney4, H. Kurtel1;
1Marmara University, School of Medicine, Sport Physiology Department, Istanbul, Turkey, 2Maltepe University, School of Medicine, Medical Biology and Genetics Department, Istanbul, Turkey, 3Marmara University, School of Dentistry, Medical Biology and Genetics Department, Istanbul, Turkey, 4Marmara University, School of Medicine, Medical Genetics Department, Istanbul, Turkey.
Presentation Number: P07.046
ACTN3 gene is responsible from the production of alpha-actinin-3 protein, which has force-generating capacity of muscle fibers, and which is restricted to fast fibers. Homozygosity for 577X in ACTN3 (R577XX) results in no production of a-actinin-3 protein. Recent studies show that elite sprint athletes had a higher frequency of the RR genotype. Aim: The purpose of the study was to investigate ACTN3 gene variations and their probable phenotypic reflection by using physiological methods, and to show ACTN3 polymorphism in Turkish soccer players (n=31). Methods: After determining the genotypes by analyzing the blood samples, three groups (XX,RR,RX) were formed. The groups were existing R577X variant in both ACTN3 genes (XX,n=4), not existing R577X variant in both ACTN3 genes (RR,n=22), or existing R577X variant only one of the two ACTN3 genes (RX,n=5), respectively. To determine aerobic performance, Bruce protocol was applied on treadmill and maximal oxygen consumption (VO2max) was measured by metabolic analyzer. On a separate day, anaerobic performance was evaluated by Wingate test. Student’s t-test or analysis of variance (ANOVA) was used for comparisons. Results: Thirteen % of the soccer players had homozygosity for R577XX codon. The VO2max levels in XX group tended to be higher from RR (p=0.09) and RX groups (p=0.05). VO2/HR (pulse oxygen) and VEmax (maximum ventilation) levels were not different between groups. Peak power values tended to be higher in RR group from the other groups. Our results evaluated the effect of genotypic variations on sprint and endurance performance of athletes contributing the understanding of genotype-phenotype correlation.
More ESHG 2008 abstracts
Study of mtDNA polymorphism in type 2 diabetes patients
S. V. Buikin1, M. V. Golubenko1, K. V. Puzyrev2, O. A. Makeeva1, I. V. Tsimbaluk3, O. A. Koshelskaja2, V. P. Puzyrev1;
1Research Institute of Medical Genetics, Tomsk, Russian Federation, 2Research Institute of Cardiology, Tomsk, Russian Federation, 3Siberian State Medical University, Tomsk, Russian Federation.
Presentation Number: P06.298
Diabetes is among frequent endocrine diseases. Endocrine system is one of energy-dependent systems in human organism. Phylogenetic mtDNA haplogroups possess different common polymorphisms and can mark effects of these variants on predisposition to common diseases. Samples of 119 type 2 diabetes patients (78 women, 41 men) and 134 healthy people were studied (all living in Tomsk region). Mean age in the groups was 52+5.5 and 47.6+10.2 years, respectively. Ultrasound examination, 24-hours monitoring of blood pressure and fasting glucose measure were performed. Comparison of frequencies of some of Europeans haplogroups (H, U, T, J) has uncovered lower frequency of haplogroup T in type 2 diabetes patients as compared to control group (OR=0.14; 0.02OR0.66; p=0.007). In the group of type 2 diabetes patients this haplogroup was detected only in two cases, whereas in control it corresponds to known frequencies for European population (11.6%). Our previous study which was conducted on patients with arterial hypertension has shown higher prevalence of haplogroup T in group of patients with left ventricular hypertrophy against patients without this complication. These alternative effects of mitochondrial haplogroup T may reflect different adaptive advantages for an individual carrying the haplogroup, in respect to different conditions. The findings suggest that particular mtDNA haplogroup (i.e. set of haplogroup-specific polymorphisms in mtDNA) may have some impact on energy metabolism and may be predisposing or protective factor for some diseases and their complications. The work was supported by Russian Foundation for Basic research (RFBR) grants 07-04-01526, 06-04-08326.
Hierarchical analysis of 28 Y-chromosome SNP’s in the population of the Republic of Macedonia
P. Noveski, S. Trivodalieva, G. D. Efremov, D. Plaseska-Karanfilska;
Macedonian Academy of Sciences and Arts, Research Centre for Genetic Engineering and Biotechnology, Skopje, Macedonia, The Former Yugoslav Republic of.
Presentation Number: P05.211
Analysis of Y-chromosome haplogroups, defined by single nucleotide polymorphisms (SNP’s), has become a standard approach for studying the origin of human populations and measuring the variability among them. Furthermore, Y-SNP’s represent a new forensic tool, because their population specificity may allow to determine the origin of any male sample of interest for forensic purposes. The aim of this study was to develop a strategy for rapid, simple and inexpensive Y-chromosome SNP’s typing in the population of R. Macedonia. We have studied a total of 343 DNA male samples; 211 Macedonians, 111 Albanians and 21 of other ethnic origin (Roma, Serbs and Turks). Methodology included multiplex PCR and single nucleotide extension reaction by SNaPshot multiplex kit. The set of 28 markers has been grouped in 5 multiplexes in order to determine the most frequent haplogroups using only 1 or 2 multiplexes. Twenty different Y haplogroups were determined among 343 male DNA samples. The finding that five haplogroups (E3b1, I1b1, J2b1a, R1a and R1b) comprise more than 70% of the Y chromosomes is consistent with the typical European Y chromosome gene pool. The distribution of the Y-haplogroups differs between Macedonians and Albanians. The most common Y haplogroup among Macedonians is I1b1 (27.5%), followed by three haplogroups present with similar frequencies E3b1 (15.6%), R1a (14.2%) and R1b (11.4%). Among Albanians the most frequent Y haplogroup is E3b1 (28.8%), followed by R1b (18.0%), J2b1a (13.5%) and R1a (12.6%).
The genetic causes of sex differences in neurodevelopmental disorders
E. Stergiakouli, H. Williams, K. Langley, A. Thapar, M. J. Owen;
Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
Presentation Number: P06.006
ADHD and schizophrenia are heritable, neurodevelopmental disorders that are more prevalent in males. Both disorders also show sex differences in age of onset and severity. The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. Animal models have associated the Y chromosome with aggression and decreased levels of serotonin and dopamine in the brain. However, due to difficulties arising from the lack of recombination and widely accepted nomenclature, the Y chromosome has been largely excluded from genetic and genomic studies of neuropsychiatric disorders. . In order to overcome this lack of knowledge we chose to study the Y chromosome in a sample of 210 cases with ADHD, 310 cases with schizophrenia and 700 U.K. controls. In total, 40 Y chromosome markers were selected to represent the main Y chromosome haplogroups that are present in the U.K. according to data from the Y chromosome Consortium data and personal communication with Y chromosome researchers. Statistical analysis of Y chromosome haplogroup analysis revealed no significantly increased representation of any haplogroup in cases with ADHD or schizophrenia compared to controls. However, this is one of the few studies to have genotyped Y chromosome markers in such a large number of U.K. individuals and therefore our results provide an insight into the population structure of U.K. Y chromosome haplogroups.
Genetic variability of Madeira archipelago inferred from Y chromosome, mtDNA and HLA system
A. C. N. Lemos, H. Spinola, R. Gonçalves, A. Fernandes, A. Brehm;
Human Genetic Laboratory, Funchal, Portugal.
Presentation Number: P07.135
The Madeira Archipelago is composed by two inhabited islands, Madeira and Porto Santo. The first settlers of these islands came from north and south of Portugal and Europe (Flandres, France and Italy), jointly with some African slaves.
Three geographic groups were defined within the Archipelago: Funchal (FX), Southwest (SW) and Northeast (NE - including Porto Santo). The Y chromosome haplogroup followed the Y Chromosome Consortium and comparison with both mtDNA and HLA-A, HLA-B and HLA-DRB1 genes was performed. Arlequin was used to compare the three geographic groups within the archipelago and to calculate genetic diversity of Y chromosome SNPs, mtDNA and HLA systems between and within each group.
No significative haplotypic differences were found regarding the Y chromosome SNPs for these three groups, opposite to mtDNA and HLA systems encountered between Southwest and Funchal. We also found major European influence although some African traces are present. The highest level of genetic diversity was found in Funchal for both mtDNA and HLAs.
The aim of this study was to determine the genetic background of the Madeira population, to search for differences within the Archipelago and find out the influence of the colonization in the actual genetic structure of this population.
The coexistence of an East-Asian mitochondrial anthropological marker and the C8270T, A8332C, and A8347C mtDNA mutations in a Hungarian family with dystonia and juvenile stroke syndrome
A. Gal1, K. Pentelenyi1, V. Remenyi1, B. Csanyi2, G. Tomory2, I. Rasko2, M. J. Molnar1,3;
1Department of Neurology, Semmelweis University, Center of Molecular Neurology, Budapest, Hungary, 2Biological Research Center, Szeged, Hungary, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Presentation Number: P05.126
The high variability of the mitochondrial genome contributes to the phenotype of the mtDNA-related disorders. MtDNA mutations have been associated with a variety of clinical manifestations. The 9-bp deletion between mtDNA 8271-8280 was originally thought to be an anthropological marker for peoples of East-Asian origin.
The proband was investigated for marked dystonic features. The clinical symptoms started after a long lasting episode of fever and elevated serum ammonia and lactate level. His brother had transient hyperkinesis, right hemiparesis. Their mother had in her childhood a stroke with aphasia and right hemiparesis. Presently she has moderate truncal ataxia, hypoacusis and cognitive dysfunction.
The mtDNA analysis of the proband found a 9bp deletion “CCCCCTCA” in the mtDNA at the position nt8271-8280, and one C8270T substitution between COII and tRNALys genes in the non-coding hypervariable segment, and two SNPs (A8332G and A8347C) in the tRNALys gene. The C8270T SNP is a pathogenic mutation, the A8332G and A8347C SNPs are not described in the literature. None of the three SNP was found in our 100 control cases. The affected Hungarian family belongs to an ancient B mitochondrial haplogroup.
Conclusion: The B haplogoup and the 9 bp small deletion indicate the east-Asian origin of this family which could be explained by the Hungarian history. The 9 bp deletion may serve as a susceptibility factor for further mtDNA alterations. We assume that the clinical symptoms are related to the pathogenic C8270T mutation and the coexistences of the A8347C and A8332G mutations may modify the clinical symptoms.
Multiple Sclerosis Disease and Mitochondria
M. Houshmand;
NIGEB, Tehran, Iran (Islamic Republic of).
Presentation Number: P05.125
Multiple Sclerosis (MS) is a multifocal demyelinating central nervous system disorder. To assess relationship between mtDNA haplogroups and MS, we have sequenced the mtDNA HVS-I in 54 MS patients and 100 control subjects. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n =10) and control subjects (n =11). The frequencies of the Asian (M, BM) and European (N, J, K) mtDNA haplogroups in five major regions of Iran was investigated. Unexpectedly, the frequencies of the Asian haplogroups M and BM were low in Iran (2.34% for haplogroup M; 17.6% for haplogroup BM and 80.06% for haplogroup N).
We have found that haplogroups A and K are significantly more abundant in MS patients (P=0.042 for haplogroup A and P=0.0005 for haplogroup K). Our findings showed that complex I activities were significantly reduced ( P=0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS. Our data suggest that Iranian tribes probably played a remarkable role in the formation of these ethnic groups. It gives the indication that the haplogroup J may be older than 6000-10000 years, and probably developed in Iran, and then expanded to different regions in Europe and Northwest Asia.
UGT1A genetic polymorphisms in São Miguel population (Azores): implications for pharmacogenetic studies
M. J. Brilhante1, P. R. Pacheco1,2, F. Sigallat1, H. Polena1, R. Cabral1,2, C. C. Branco1,2, L. Mota-Vieira1,2;
1Hospital of Divino Espirito Santo of Ponta Delgada, Azores, Portugal, 2Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Presentation Number: P07.127
UGT enzymes are responsible for glucuronidation and detoxification of endogenous and exogenous compounds. Homozygosity for a polymorphism in the UGT1A1 TATAA box promoter causes Gilbert’s syndrome. This sequence contains six TA repeats (UGT1A1*1), whereas seven repeats (UGT1A1*28) imply reduced gene expression. In UGT1A6, two missense mutations result in three alleles: UGT1A6*1 (T181-R184), UGT1A6*2 (A181-S184) and UGT1A6*3 (T181-S184). UGT1A1*28 and UGT1A6*2 are associated with reduced enzymatic activity.
Here, we determined UGT1A1 and UGT1A6 polymorphisms prevalence in São Miguel population (n=469 healthy individuals), and investigated UGT1A1 association with UGT1A6 polymorphisms. In UGT1A1, we identified five genotypes: 0.4% (TA)5/(TA)6, 50.5% (TA)6/(TA)6, 39.7% (TA)6/(TA)7, 9.2% (TA)7/(TA)7 and 0.2% (TA)6/(TA)8. Five and eight TA repeats are found only in African-ancestry individuals. These alleles confirm our previous results on Sao Miguel genetic ancestry, an admixed population composed of European, Jews and Africans. UGT1A*6 genotype frequencies were 47.5% (*1*1), 36.2%, (*1*2), 7.5% (*2*2), 4.7% (*1*3) and 4.1% (2*3). A strong association between UGT1A1*28 and UGT1A6*2 alleles was observed, since 81.4% homozygous for UGT1A1*28 were also homozygous for UGT1A6*2. Overall, 6.7% were homozygous for both UGT1 polymorphisms, and 39% had at least one variant allele for UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms result in modified expression and activity of UGTs, may influence susceptibility to cancers and predispose to side effects of drugs, such as irinotecan. Currently, we are analyzing three missense mutations in UGT1A7, to evaluate the extension of linkage disequilibrium between UGT1A1, UGT1A6 and UGT1A7. Funded by Azorean Government (M1.2.1./I/003/2005). PRP has PhD grant SFRH/BD/27453/2006.
The 8q24 rs10505470 variant is not associated with prostate cancer risk in patients from the Republic of Macedonia
N. Matevska1, D. Petrovski2, S. Dzikova2, S. Banev2, V. Georgiev2, A. Sikole2, A. J. Dimovski1;
1Faculty of Pharmacy, Skopje, The former Yugoslav Republic of Macedonia, 2Faculty of Medicine, Skopje, The former Yugoslav Republic of Macedonia.
Presentation Number: P04.181
Recent compelling evidence demonstrates chromosome 8q24 as a prostate cancer (PC) susceptibility locus. Multiple variants within three adjacent regions at 8q24 have been identified to impact the risk of PC. Most commonly assessed variants are rs1447295 (region1), rs16901979 (region2) and rs6983267 (region3). Although regions 1 and 3 are close together, they are separated by a recombination hotspot among individuals of European ancestry. Hence, all three neighboring regions seem to contribute independently to the PC risk, and the combined effects of SNPs across regions follow a multiplicative model. In order to examine the association between the PC risk and all three regions of 8q24 we designed a case-control study of randomly selected PC patients and controls without history of any malignant disease. Herein, we present the results of the association of PC risk and rs10505470 variant which is known to be in strong LD with rs6983267 in region 3. The rs10505470 genotypes were determined using custom designed TaqMan SNP genotyping assay on a Real-time PCR analyzer (MxPro 3005P). We did not observe a difference in overall allelic frequencies and genotype distribution {(A allele 0.518 for patients; 0.516 for controls); (AA 28.24%, AG 47.06%, GG 24.71% for patients; AA 27.60%, AG 47.92%, GG 24.48% for controls)}. Furthermore there was no significant difference after stratification of patients in subgroups according to age and Gleason score. Our findings led us to conclude that rs10505470 variant is not implicated with PC risk, time of onset or PC aggressiveness in Macedonian population.
Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population
H. Kokotas1, L. Van Laer2, M. Grigoriadou1, V. Iliadou3, J. Economides4, S. Pomoni1, A. Pampanos1, N. Eleftheriades5, E. Ferekidou6, S. Korres6, A. Giannoulia-Karantana7, G. Van Camp2, M. B. Petersen1;
1Institute of Child Health, Athens, Greece, 2University of Antwerp, Antwerp, Belgium, 3AHEPA Hospital, Thessaloniki, Greece, 4‘Aghia Sophia’ Children’s Hospital, Athens, Greece, 5St. Loukas Hospital, Thessaloniki, Greece, 6Athens University, Athens, Greece, 7Athens University Medical School, Athens, Greece.
Presentation Number: P06.080
Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to forty percent of autosomal recessive, congenital, severe to profound hearing impairment cases result from mutations in a single gene, GJB2. The 35delG mutation accounts for the majority of GJB2 mutations detected in Caucasian populations and represents one of the most frequent disease mutations identified so far. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, whilst other studies support the theory of a common founder. Greece is amongst the countries presenting high frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers, mapping within or flanking the GJB2 gene, as compared to 60 Greek hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene, at distances of 34 kb on the centromeric and 90 kb on the telomeric side of the gene, respectively. Our study supports the hypothesis of a founder effect and we further propose that ethnic groups of Greek ancestry could have propagated the 35delG mutation, as evidenced by historical data beginning from the 15th century BC.
Variants in the Vitamin D Receptor Gene and Melanoma Etiology
L. P. Fernandez1, E. Barroso1, R. L. Milne1, G. Pita1, M. Tanic1, J. A. Aviles2, P. Lazaro2, J. Benitez1, G. Ribas1;
1Spanish National Cancer Research Centre (CNIO), Madrid, Spain, 2Hospital Gregorio Marañon, Madrid, Spain.
Presentation Number: P07.086
The aetiology of malignant melanoma (MM) remains unclear but it is known that both genetic and environmental factors influence the development of sporadic disease. The main reason for the increasing incidence of MM in the general population is greater sun exposure. Epidemiologic studies confirm that UV radiation is the main factor involved in the pathogenesis of the disease. Among phenotypic factors, fair pigmentation and low tanning ability are the most important risk factors. In recent years there has been a increasing interest in the role of vitamin D and its active metabolites in MM susceptibility. Sunlight induces production of vitamin D that has been associated with antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma cells mediated through the vitamin D receptor. In this study we explore the interaction between sunlight exposure and vitamin D receptor gene polymorphisms in the etiology of MM.
This case-control study included 131 consecutive Spanish MM patients from the Dermatology Unit of the Gregorio Marañón Hospital and 245 control subjects frequency matched for sex and age. Phenotypic information was collected using a standardized questionnaire.
Four SNPs in the vitamin D receptor gene (VDR) were genotyped. SNPs on exons or in the putative promoter region were selected. We were able to identify several individual SNPs and haplotypes associated with tumoral characteristics such as breslow index and melanoma location. We also discuss the role of VDR variants as possible markers for MM and its agresiveness.
Natural Background Radiation Dictates Extensive Structural Polymorphism in the Human Y-Chromosome
S. Premi, J. Srivastava, S. Ali;
National Institute of Immunology, Delhi, India.
Presentation Number: P07.029
Ionizing radiations are known to affect the human genome but its impact on human Y chromosome still remains unaddressed. Here we analyze 300 males residing in an area containing the world’s highest level of natural background radiation (NBR) and 390 controls from different parts of India. Random microdeletions were observed in 95% of the NBR exposed males with higher frequency in AZFc region but without gr/gr or b2/b4 phenotypes. Scrutiny of the male fertility associated genes showed copy number polymorphism (CNP) and tandem duplication in 84%, and exclusive deletion of DBY in 25% of the exposed males. Detailed analysis revealed multiple polymorphic copies of SRY and CDY1 genes in addition to several known and novel mutations of the SRY gene. Amongst NBR exposed males with multiples copies of the DAZ genes, 75% showed varying FISH signals for DAZ genes with unilocus or bilocus duplications whereas 30% showed mosaicism in terms of presence/absence of the signals in 6-8% cells and unexpected number of signals in 9-12% interphase nuclei. Interestingly, all these alterations were exclusively somatic in nature substantiating normal fertility status of NBR exposed males. Though the actual mechanism is not known, we hypothesize that some putative innate protective mechanisms are operative in germline to counteract the effect of NBR. Analysis of additional Y linked loci may uncover the overall impact of NBR on the structural and functional attributes of this chromosome.
Persons with greater individual genome-wide heterozygosity show lower increase of cortisol levels during acute psychological stress
L. Zgaga1, C. Hayward2, Z. Biloglav1, I. Kolcic1, O. Polasek1,3, D. Rudan4, A. Vorko-Jovic1, A. Wright2, H. Campbell3, I. Rudan3;
1Medical School, University of Zagreb, Zagreb, Croatia, 2MRC Human Genetics Unit, Edinburgh, United Kingdom, 3Faculty of Medicine, Edinburgh, United Kingdom, 4Dubrava University Hospital, Zagreb, Croatia.
Presentation Number: P07.061
Aim: Genome-wide heterozygosity (GWH) was reported to affect a range of quantitative traits in humans, animals and plants. Several studies suggested that the underlying mechanism is increased compensation potential to environmental stressors in outbred individuals. In humans, psychological stress has been consistently linked to an increase in cortisol levels, which eventually impairs immune system function. We studied whether GWH status affects the increase in cortisol levels in persons reporting acute psychological stress.
Materials and methods: We studied 1,026 examinees from the Vis island, Croatia. Standardised multilocus heterozygosity (sMLH) was computed for each person from a genome-wide scan using 317.000 single nucleotide polymorphisms. Morning cortisol level was measured from the blood in all participants. Reported acute psychological stress was measured using General Health Questionnaire 30 (GHQ-30).
Results: GHQ-30 scores had a significant effect on the increase of cortisol (p<0.001). All examinees were therefore categorized in 3 groups according to the increasing levels of reported psychological stress within GHQ-30. In all groups, the effect of sMLH on cortisol levels was investigated using general linear model with inclusion of potential confounding variables. In the group reporting mild stress the effect was weak and non-significant (Beta=-0.058, p=0.34), but with increase of reported stress levels to moderate and strong, the effect became larger and statistically significant (Beta =-0.125, p=0.003; and Beta=-0.188, p=0.04, respectively).
Conclusion: This study implies that, in humans, the increase in individual GWH may buffer the effects of psychological stress on cortisol levels, thus protecting the physiological function of immune and endocrine system.
Comparison of genome-wide homozygosity-by-descent estimates in human isolated population
O. Polasek1,2, I. Kolc(ic'2, L. Zgaga2, Z. Biloglav2, A. Vorko Jovic'2, D. Rudan3, I. Rudan4, A. Wright5, H. Campbell1, A. Leutenegger6,7;
1Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom, 2Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia, 3Clinical Hospital Dubrava, Zagreb, Croatia, 4Centre for Global Health, University of Split, Split, Croatia, 5Human Genetics Unit, Medical Research Council, Edinburgh, United Kingdom, 6Inserm U535, Villejuif, France, 7Univ. Paris-Sud, Villejuif, France.
Presentation Number: P07.068
The aim of this study was to investigate several methods of marker based genome-wide homozygosity estimation. The study sample consisted of 118 members of a single extended family living on the Adriatic Croatian island of Vis, where no pedigree based inbreeding was observed, and therefore no homozygosity by descent, HBD, was expected. Individuals were genotyped for 810 microsatellite markers and a 317k Illumina chip. Five approaches were compared: the proportion of heterozygous loci (multilocus heterozygosity, MLH), two methods of moments approaches that use different weighting approaches (ADC and PLINK), and finally 2 maximum likelihood approaches, one singlepoint and the other multipoint, using a hidden Markov model for marker dependencies (FEstim). The latter is the only existing multipoint method for HBD estimation and gives estimates the closest to the true HBD values, as shown previously in a simulation study. The results indicated that the two methods of moments approaches correlated highly with MLH and hence did not bring much information about HBD. On the other hand, the two maximum likelihood approaches exhibited zero value estimates when homozygosity was likely due to chance. A total of 68 individuals (57.6%) had no HBD as defined by the FEstim, while a total of 4 individuals (3.9%) had FEstim values over 0.0625 indicating inbreeding closer than first cousins. These methods can be used to differentiate homozygosity by chance vs. HBD, which may be important in investigation of the genome-wide heterozygosity effects on quantitative and health related traits.
Genetic differentiation of ethnic groups of Russia evaluated by genes of hereditary disorders
R. A. Zinchenko, V. A. Galkina, E. K. Ginter;
Research Center for Medical Genetics, ??scow, Russian Federation.
Presentation Number: P07.057
On the basis of genetic epidemiological study the prevalence of autosomal dominant, autosomal recessive and X-linked recessive disorders in 10 regions of Russia (5 ethnic groups: Russians, Maris, Chuvashs, Udmurts, Adighes) was estimated. The size of the investigated population was more than 2.5 millions of persons. Genetic differentiation between populations of different hierarchical levels by estimated loads of hereditary diseases was established. The prevalence rate of all Mendelian disorders varied in the investigated populations from 1.34 to 5.92 per 1000 persons. Genetic diversity of hereditary diseases in the investigated populations was also under our study. 199 autosomal dominant, 165 autosomal recessive and 48 X-linked recessive diseases were revealed. Most of them were rare or very rare. There were some cases of local accumulations of hereditary disorders in the investigated populations. Simultaneously with medical genetic study the population genetic study was performed in the populations. By comparing both studies it was suggested that the genetic drift is a most important factor which determines genetic differentiation of populations by the prevalence and genetic diversity of autosomal disorders.
Genetic care of families affected by albinism in an African cultural context
P. M. Lund;
Coventry University, Coventry, United Kingdom.
Presentation Number: P09.47
The birth of a baby with the autosomal recessive condition oculocutaneous albinism (OCA) in a black African population is often traumatic for the mother as the phenotype, with hypopigmentation of the hair, skin and eyes, differs so visibly from the normal level of pigmentation in this group. The incidence of OCA among the Venda of northern South Africa is relatively high, with 1 in 1970 affected, giving a carrier rate of 1 in 23. Myth and superstition surround OCA, with affected families believing they have been bewitched. The experiences of genetic nurses at the large regional hospitals in Venda and of families who have benefited from their genetic counselling services are explored via semi structured interviews. The genetic nurses, based in the midwifery section, identify affected babies as part of the National Birth Surveillance Programme and intervene immediately to inform the mother of the special health care needs of her baby. They explain the genetic causes of OCA and aim to empower her to counter negative attitudes she is likely to encounter from her family, who may accuse her of infidelity, and the wider community when returning to her rural home. Barriers to the provision of genetic care in this remote, rural region and strategies adopted by health care professionals to overcome these difficulties are explored. This genetic practice is a model for providing care to those affected by genetic conditions in rural, low resources regions of the world.
MC1R polymorphisms, phenotype and UVB radiation sensitivity in melanoma risk patients
P. Aguilera1, C. Carrera1, G. Salerni1, F. Cuellar1, Z. Ogbah2, J. A. Puig-Butille2, M. Lecha3, J. Malvehy1, S. Puig1;
1Melanoma Unit, Barcelona, Spain, 2Melanoma Unit, Genetic Service, Barcelona, Spain, 3Photobiology and Phototherapy Unit, Dermatology Service, Barcelona, Spain.
Presentation Number: P04.161
Background: UV radiation (UVR) plays an important role in melanocytic tumours development. History of intense intermittent sun-exposure, phenotypic characteristics encoding melanocortin-1 receptor gene (MC1R) and the presence of multiple nevi are risk markers to develop malignant melanoma. Familiar melanoma represents 10% of all melanomas and it is supposed that genetic burden in these patients plays a more important role than environmental factors.
Objective: to study in different melanoma-risk patient settings the association between phenotypic characteristics, number of nevi, UVR sensitivity and polymorphisms in MC1R.
Methods: two groups of high risk melanoma patients were studied (N=32):
Group 1: Dysplastic nevus syndrome (DNS) patients (N=23).
Group 2: Melanoma patients belonging to familial melanoma (N=9).
UVB sensitivity, phenotypic and genotypic characterization were performed.
Results: patients from DNS had a higher UV-B photosensitivity (reduced UV-B minimal erythemal dose) compared with patients from familiar melanoma group (mean 88mJ/cm2± 26 vs 122 mJ/cm2 ± 26; p<0,005). In both groups a high percentage of MC1R polymorphisms were detected (at least 1 polymorphism in 75% of patients in group 1 vs 78% in group 2). However, a different percentage of red hair type polymorphisms (RHP) was observed in the 2 groups (20% in group 1 vs 66% in group 2, p<0,01).
Conclusions: Patients affected by DNS presented high UV-B sensitivity, similar to North European populations or patients with photo-dermatoses. Similar percentage of MC1R polymorphisms were detected in our both samples, however, RHPs were strongly associated with familial melanoma, an unexpected result in our Mediterranean area.
Super-hotspots for Meiotic Recombination in the Human Genome
Presentation Time: Tuesday, 11:00 a.m. - 11:15 a.m.
I. L. Berg, A. J. Webb, A. J. Jeffreys;
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
Presentation Number: C13.2
Homologous recombination is a vital process for ensuring proper chromosome segregation during meiosis, as well as increasing diversity by reshuffling haplotypes between generations. In this study, we analysed Phase II HapMap data to identify autosomal regions showing extreme breakdown of linkage disequilibrium (LD). Sixteen of these regions were selected for crossover analysis directly in sperm. All contained active sperm hotspots, with similar characteristics as at previously studied hotspots, i.e. normally-distributed crossover breakpoints within regions 1-2 kb wide. These new hotspots were on average 10 fold more active than previously characterised autosomal hotspots and include the most active crossover hotspots yet discovered in the human genome. Their activity is however poorly predicted from LD data. Most crossovers in these hotspots were simple, exchanging haplotypes within a single interval between markers. However, 0.3% of exchanges were more complex, switching haplotypes at several intervals during an exchange event. Most of these occurred within the boundaries of the hotspot while 22% occurred beyond the hotpot, implying a broader region involved during intermediate stages of recombination. Several hotspots showed crossover frequency variation between men, including two cases of complete presence/absence polymorphism. Instances of extreme or subtle biased gene conversion accompanying crossover were observed within some hotspots, in some cases correlating with crossover frequency variation between men. Curiously none of the most active hotpots showed polymorphism or strongly biased conversion, in contrast to the prediction that these hotpots should be the most vulnerable to attenuation/extinction by meiotic drive in favour of recombination suppressors.
G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth
Presentation Time: Saturday, 7:00 p.m. - 7:15 p.m.
S. M. Pasternack1, I. von Kügelgen2, K. Al Aboud3, Y. Lee4,5, F. Rüschendorf5, K. Voss6, A. M. Hillmer7, G. J. Molderings2, T. Franz8, A. Ramirez9,10, P. Nürnberg10,11, M. M. Nöthen1,7, R. C. Betz1;
1Institute of Human Genetics, Bonn, Germany, 2Department of Pharmacology, Bonn, Germany, 3Department of Dermatology, Makkah, Saudi Arabia, 4Department of Pediatric Pneumology and Immunology, Berlin, Germany, 5Max Delbrück Center for Molecular Medicine, Berlin, Germany, 6Department of Human Genetics, Würzburg, Germany, 7Department of Genomics, Bonn, Germany, 8Department of Anatomy, Bonn, Germany, 9Institute of Human Genetics, Cologne, Germany, 10Center for Molecular Medicine Cologne, Cologne, Germany, 11Cologne Center for Genomics, Cologne, Germany.
Presentation Number: PL2.3
Hypotrichosis simplex (MIM 146520 and MIM 605389) is a group of hereditary non-syndromic human alopecias that affects men and women equally. The hair loss is diffuse and progressive, and usually begins in early childhood. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, a gene which encodes an orphan G protein-coupled receptor. We analysed expression-patterns of P2RY5 in various human and mouse tissues and performed western blot and immunofluorescence analyses to characterize the protein. Furthermore, we identified oleoyl-L-a-lysophosphatidic acid (LPA), a bioactive lipid, as being a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signalling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. As P2RY5 is expressed in human hair follicle cells, but LPA4 and LPA5 are not, a loss of P2Y5 function will not be compensated for, and will ultimately lead to pathological changes and hair loss.
Our study is the first to implicate a G protein-coupled receptor as being essential for and specific to the maintenance of human hair growth. With the functional characterization of the P2Y5 receptor, we identify the missing link which is required for the transmission of the LPA signal through the cell membrane in hair follicle cells. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans.
S. V. Buikin1, M. V. Golubenko1, K. V. Puzyrev2, O. A. Makeeva1, I. V. Tsimbaluk3, O. A. Koshelskaja2, V. P. Puzyrev1;
1Research Institute of Medical Genetics, Tomsk, Russian Federation, 2Research Institute of Cardiology, Tomsk, Russian Federation, 3Siberian State Medical University, Tomsk, Russian Federation.
Presentation Number: P06.298
Diabetes is among frequent endocrine diseases. Endocrine system is one of energy-dependent systems in human organism. Phylogenetic mtDNA haplogroups possess different common polymorphisms and can mark effects of these variants on predisposition to common diseases. Samples of 119 type 2 diabetes patients (78 women, 41 men) and 134 healthy people were studied (all living in Tomsk region). Mean age in the groups was 52+5.5 and 47.6+10.2 years, respectively. Ultrasound examination, 24-hours monitoring of blood pressure and fasting glucose measure were performed. Comparison of frequencies of some of Europeans haplogroups (H, U, T, J) has uncovered lower frequency of haplogroup T in type 2 diabetes patients as compared to control group (OR=0.14; 0.02OR0.66; p=0.007). In the group of type 2 diabetes patients this haplogroup was detected only in two cases, whereas in control it corresponds to known frequencies for European population (11.6%). Our previous study which was conducted on patients with arterial hypertension has shown higher prevalence of haplogroup T in group of patients with left ventricular hypertrophy against patients without this complication. These alternative effects of mitochondrial haplogroup T may reflect different adaptive advantages for an individual carrying the haplogroup, in respect to different conditions. The findings suggest that particular mtDNA haplogroup (i.e. set of haplogroup-specific polymorphisms in mtDNA) may have some impact on energy metabolism and may be predisposing or protective factor for some diseases and their complications. The work was supported by Russian Foundation for Basic research (RFBR) grants 07-04-01526, 06-04-08326.
Hierarchical analysis of 28 Y-chromosome SNP’s in the population of the Republic of Macedonia
P. Noveski, S. Trivodalieva, G. D. Efremov, D. Plaseska-Karanfilska;
Macedonian Academy of Sciences and Arts, Research Centre for Genetic Engineering and Biotechnology, Skopje, Macedonia, The Former Yugoslav Republic of.
Presentation Number: P05.211
Analysis of Y-chromosome haplogroups, defined by single nucleotide polymorphisms (SNP’s), has become a standard approach for studying the origin of human populations and measuring the variability among them. Furthermore, Y-SNP’s represent a new forensic tool, because their population specificity may allow to determine the origin of any male sample of interest for forensic purposes. The aim of this study was to develop a strategy for rapid, simple and inexpensive Y-chromosome SNP’s typing in the population of R. Macedonia. We have studied a total of 343 DNA male samples; 211 Macedonians, 111 Albanians and 21 of other ethnic origin (Roma, Serbs and Turks). Methodology included multiplex PCR and single nucleotide extension reaction by SNaPshot multiplex kit. The set of 28 markers has been grouped in 5 multiplexes in order to determine the most frequent haplogroups using only 1 or 2 multiplexes. Twenty different Y haplogroups were determined among 343 male DNA samples. The finding that five haplogroups (E3b1, I1b1, J2b1a, R1a and R1b) comprise more than 70% of the Y chromosomes is consistent with the typical European Y chromosome gene pool. The distribution of the Y-haplogroups differs between Macedonians and Albanians. The most common Y haplogroup among Macedonians is I1b1 (27.5%), followed by three haplogroups present with similar frequencies E3b1 (15.6%), R1a (14.2%) and R1b (11.4%). Among Albanians the most frequent Y haplogroup is E3b1 (28.8%), followed by R1b (18.0%), J2b1a (13.5%) and R1a (12.6%).
The genetic causes of sex differences in neurodevelopmental disorders
E. Stergiakouli, H. Williams, K. Langley, A. Thapar, M. J. Owen;
Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
Presentation Number: P06.006
ADHD and schizophrenia are heritable, neurodevelopmental disorders that are more prevalent in males. Both disorders also show sex differences in age of onset and severity. The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. Animal models have associated the Y chromosome with aggression and decreased levels of serotonin and dopamine in the brain. However, due to difficulties arising from the lack of recombination and widely accepted nomenclature, the Y chromosome has been largely excluded from genetic and genomic studies of neuropsychiatric disorders. . In order to overcome this lack of knowledge we chose to study the Y chromosome in a sample of 210 cases with ADHD, 310 cases with schizophrenia and 700 U.K. controls. In total, 40 Y chromosome markers were selected to represent the main Y chromosome haplogroups that are present in the U.K. according to data from the Y chromosome Consortium data and personal communication with Y chromosome researchers. Statistical analysis of Y chromosome haplogroup analysis revealed no significantly increased representation of any haplogroup in cases with ADHD or schizophrenia compared to controls. However, this is one of the few studies to have genotyped Y chromosome markers in such a large number of U.K. individuals and therefore our results provide an insight into the population structure of U.K. Y chromosome haplogroups.
Genetic variability of Madeira archipelago inferred from Y chromosome, mtDNA and HLA system
A. C. N. Lemos, H. Spinola, R. Gonçalves, A. Fernandes, A. Brehm;
Human Genetic Laboratory, Funchal, Portugal.
Presentation Number: P07.135
The Madeira Archipelago is composed by two inhabited islands, Madeira and Porto Santo. The first settlers of these islands came from north and south of Portugal and Europe (Flandres, France and Italy), jointly with some African slaves.
Three geographic groups were defined within the Archipelago: Funchal (FX), Southwest (SW) and Northeast (NE - including Porto Santo). The Y chromosome haplogroup followed the Y Chromosome Consortium and comparison with both mtDNA and HLA-A, HLA-B and HLA-DRB1 genes was performed. Arlequin was used to compare the three geographic groups within the archipelago and to calculate genetic diversity of Y chromosome SNPs, mtDNA and HLA systems between and within each group.
No significative haplotypic differences were found regarding the Y chromosome SNPs for these three groups, opposite to mtDNA and HLA systems encountered between Southwest and Funchal. We also found major European influence although some African traces are present. The highest level of genetic diversity was found in Funchal for both mtDNA and HLAs.
The aim of this study was to determine the genetic background of the Madeira population, to search for differences within the Archipelago and find out the influence of the colonization in the actual genetic structure of this population.
The coexistence of an East-Asian mitochondrial anthropological marker and the C8270T, A8332C, and A8347C mtDNA mutations in a Hungarian family with dystonia and juvenile stroke syndrome
A. Gal1, K. Pentelenyi1, V. Remenyi1, B. Csanyi2, G. Tomory2, I. Rasko2, M. J. Molnar1,3;
1Department of Neurology, Semmelweis University, Center of Molecular Neurology, Budapest, Hungary, 2Biological Research Center, Szeged, Hungary, 3Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Presentation Number: P05.126
The high variability of the mitochondrial genome contributes to the phenotype of the mtDNA-related disorders. MtDNA mutations have been associated with a variety of clinical manifestations. The 9-bp deletion between mtDNA 8271-8280 was originally thought to be an anthropological marker for peoples of East-Asian origin.
The proband was investigated for marked dystonic features. The clinical symptoms started after a long lasting episode of fever and elevated serum ammonia and lactate level. His brother had transient hyperkinesis, right hemiparesis. Their mother had in her childhood a stroke with aphasia and right hemiparesis. Presently she has moderate truncal ataxia, hypoacusis and cognitive dysfunction.
The mtDNA analysis of the proband found a 9bp deletion “CCCCCTCA” in the mtDNA at the position nt8271-8280, and one C8270T substitution between COII and tRNALys genes in the non-coding hypervariable segment, and two SNPs (A8332G and A8347C) in the tRNALys gene. The C8270T SNP is a pathogenic mutation, the A8332G and A8347C SNPs are not described in the literature. None of the three SNP was found in our 100 control cases. The affected Hungarian family belongs to an ancient B mitochondrial haplogroup.
Conclusion: The B haplogoup and the 9 bp small deletion indicate the east-Asian origin of this family which could be explained by the Hungarian history. The 9 bp deletion may serve as a susceptibility factor for further mtDNA alterations. We assume that the clinical symptoms are related to the pathogenic C8270T mutation and the coexistences of the A8347C and A8332G mutations may modify the clinical symptoms.
Multiple Sclerosis Disease and Mitochondria
M. Houshmand;
NIGEB, Tehran, Iran (Islamic Republic of).
Presentation Number: P05.125
Multiple Sclerosis (MS) is a multifocal demyelinating central nervous system disorder. To assess relationship between mtDNA haplogroups and MS, we have sequenced the mtDNA HVS-I in 54 MS patients and 100 control subjects. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n =10) and control subjects (n =11). The frequencies of the Asian (M, BM) and European (N, J, K) mtDNA haplogroups in five major regions of Iran was investigated. Unexpectedly, the frequencies of the Asian haplogroups M and BM were low in Iran (2.34% for haplogroup M; 17.6% for haplogroup BM and 80.06% for haplogroup N).
We have found that haplogroups A and K are significantly more abundant in MS patients (P=0.042 for haplogroup A and P=0.0005 for haplogroup K). Our findings showed that complex I activities were significantly reduced ( P=0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS. Our data suggest that Iranian tribes probably played a remarkable role in the formation of these ethnic groups. It gives the indication that the haplogroup J may be older than 6000-10000 years, and probably developed in Iran, and then expanded to different regions in Europe and Northwest Asia.
UGT1A genetic polymorphisms in São Miguel population (Azores): implications for pharmacogenetic studies
M. J. Brilhante1, P. R. Pacheco1,2, F. Sigallat1, H. Polena1, R. Cabral1,2, C. C. Branco1,2, L. Mota-Vieira1,2;
1Hospital of Divino Espirito Santo of Ponta Delgada, Azores, Portugal, 2Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Presentation Number: P07.127
UGT enzymes are responsible for glucuronidation and detoxification of endogenous and exogenous compounds. Homozygosity for a polymorphism in the UGT1A1 TATAA box promoter causes Gilbert’s syndrome. This sequence contains six TA repeats (UGT1A1*1), whereas seven repeats (UGT1A1*28) imply reduced gene expression. In UGT1A6, two missense mutations result in three alleles: UGT1A6*1 (T181-R184), UGT1A6*2 (A181-S184) and UGT1A6*3 (T181-S184). UGT1A1*28 and UGT1A6*2 are associated with reduced enzymatic activity.
Here, we determined UGT1A1 and UGT1A6 polymorphisms prevalence in São Miguel population (n=469 healthy individuals), and investigated UGT1A1 association with UGT1A6 polymorphisms. In UGT1A1, we identified five genotypes: 0.4% (TA)5/(TA)6, 50.5% (TA)6/(TA)6, 39.7% (TA)6/(TA)7, 9.2% (TA)7/(TA)7 and 0.2% (TA)6/(TA)8. Five and eight TA repeats are found only in African-ancestry individuals. These alleles confirm our previous results on Sao Miguel genetic ancestry, an admixed population composed of European, Jews and Africans. UGT1A*6 genotype frequencies were 47.5% (*1*1), 36.2%, (*1*2), 7.5% (*2*2), 4.7% (*1*3) and 4.1% (2*3). A strong association between UGT1A1*28 and UGT1A6*2 alleles was observed, since 81.4% homozygous for UGT1A1*28 were also homozygous for UGT1A6*2. Overall, 6.7% were homozygous for both UGT1 polymorphisms, and 39% had at least one variant allele for UGT1A1*28 and UGT1A6*2. These highly prevalent polymorphisms result in modified expression and activity of UGTs, may influence susceptibility to cancers and predispose to side effects of drugs, such as irinotecan. Currently, we are analyzing three missense mutations in UGT1A7, to evaluate the extension of linkage disequilibrium between UGT1A1, UGT1A6 and UGT1A7. Funded by Azorean Government (M1.2.1./I/003/2005). PRP has PhD grant SFRH/BD/27453/2006.
The 8q24 rs10505470 variant is not associated with prostate cancer risk in patients from the Republic of Macedonia
N. Matevska1, D. Petrovski2, S. Dzikova2, S. Banev2, V. Georgiev2, A. Sikole2, A. J. Dimovski1;
1Faculty of Pharmacy, Skopje, The former Yugoslav Republic of Macedonia, 2Faculty of Medicine, Skopje, The former Yugoslav Republic of Macedonia.
Presentation Number: P04.181
Recent compelling evidence demonstrates chromosome 8q24 as a prostate cancer (PC) susceptibility locus. Multiple variants within three adjacent regions at 8q24 have been identified to impact the risk of PC. Most commonly assessed variants are rs1447295 (region1), rs16901979 (region2) and rs6983267 (region3). Although regions 1 and 3 are close together, they are separated by a recombination hotspot among individuals of European ancestry. Hence, all three neighboring regions seem to contribute independently to the PC risk, and the combined effects of SNPs across regions follow a multiplicative model. In order to examine the association between the PC risk and all three regions of 8q24 we designed a case-control study of randomly selected PC patients and controls without history of any malignant disease. Herein, we present the results of the association of PC risk and rs10505470 variant which is known to be in strong LD with rs6983267 in region 3. The rs10505470 genotypes were determined using custom designed TaqMan SNP genotyping assay on a Real-time PCR analyzer (MxPro 3005P). We did not observe a difference in overall allelic frequencies and genotype distribution {(A allele 0.518 for patients; 0.516 for controls); (AA 28.24%, AG 47.06%, GG 24.71% for patients; AA 27.60%, AG 47.92%, GG 24.48% for controls)}. Furthermore there was no significant difference after stratification of patients in subgroups according to age and Gleason score. Our findings led us to conclude that rs10505470 variant is not implicated with PC risk, time of onset or PC aggressiveness in Macedonian population.
Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population
H. Kokotas1, L. Van Laer2, M. Grigoriadou1, V. Iliadou3, J. Economides4, S. Pomoni1, A. Pampanos1, N. Eleftheriades5, E. Ferekidou6, S. Korres6, A. Giannoulia-Karantana7, G. Van Camp2, M. B. Petersen1;
1Institute of Child Health, Athens, Greece, 2University of Antwerp, Antwerp, Belgium, 3AHEPA Hospital, Thessaloniki, Greece, 4‘Aghia Sophia’ Children’s Hospital, Athens, Greece, 5St. Loukas Hospital, Thessaloniki, Greece, 6Athens University, Athens, Greece, 7Athens University Medical School, Athens, Greece.
Presentation Number: P06.080
Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to forty percent of autosomal recessive, congenital, severe to profound hearing impairment cases result from mutations in a single gene, GJB2. The 35delG mutation accounts for the majority of GJB2 mutations detected in Caucasian populations and represents one of the most frequent disease mutations identified so far. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, whilst other studies support the theory of a common founder. Greece is amongst the countries presenting high frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers, mapping within or flanking the GJB2 gene, as compared to 60 Greek hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene, at distances of 34 kb on the centromeric and 90 kb on the telomeric side of the gene, respectively. Our study supports the hypothesis of a founder effect and we further propose that ethnic groups of Greek ancestry could have propagated the 35delG mutation, as evidenced by historical data beginning from the 15th century BC.
Variants in the Vitamin D Receptor Gene and Melanoma Etiology
L. P. Fernandez1, E. Barroso1, R. L. Milne1, G. Pita1, M. Tanic1, J. A. Aviles2, P. Lazaro2, J. Benitez1, G. Ribas1;
1Spanish National Cancer Research Centre (CNIO), Madrid, Spain, 2Hospital Gregorio Marañon, Madrid, Spain.
Presentation Number: P07.086
The aetiology of malignant melanoma (MM) remains unclear but it is known that both genetic and environmental factors influence the development of sporadic disease. The main reason for the increasing incidence of MM in the general population is greater sun exposure. Epidemiologic studies confirm that UV radiation is the main factor involved in the pathogenesis of the disease. Among phenotypic factors, fair pigmentation and low tanning ability are the most important risk factors. In recent years there has been a increasing interest in the role of vitamin D and its active metabolites in MM susceptibility. Sunlight induces production of vitamin D that has been associated with antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma cells mediated through the vitamin D receptor. In this study we explore the interaction between sunlight exposure and vitamin D receptor gene polymorphisms in the etiology of MM.
This case-control study included 131 consecutive Spanish MM patients from the Dermatology Unit of the Gregorio Marañón Hospital and 245 control subjects frequency matched for sex and age. Phenotypic information was collected using a standardized questionnaire.
Four SNPs in the vitamin D receptor gene (VDR) were genotyped. SNPs on exons or in the putative promoter region were selected. We were able to identify several individual SNPs and haplotypes associated with tumoral characteristics such as breslow index and melanoma location. We also discuss the role of VDR variants as possible markers for MM and its agresiveness.
Natural Background Radiation Dictates Extensive Structural Polymorphism in the Human Y-Chromosome
S. Premi, J. Srivastava, S. Ali;
National Institute of Immunology, Delhi, India.
Presentation Number: P07.029
Ionizing radiations are known to affect the human genome but its impact on human Y chromosome still remains unaddressed. Here we analyze 300 males residing in an area containing the world’s highest level of natural background radiation (NBR) and 390 controls from different parts of India. Random microdeletions were observed in 95% of the NBR exposed males with higher frequency in AZFc region but without gr/gr or b2/b4 phenotypes. Scrutiny of the male fertility associated genes showed copy number polymorphism (CNP) and tandem duplication in 84%, and exclusive deletion of DBY in 25% of the exposed males. Detailed analysis revealed multiple polymorphic copies of SRY and CDY1 genes in addition to several known and novel mutations of the SRY gene. Amongst NBR exposed males with multiples copies of the DAZ genes, 75% showed varying FISH signals for DAZ genes with unilocus or bilocus duplications whereas 30% showed mosaicism in terms of presence/absence of the signals in 6-8% cells and unexpected number of signals in 9-12% interphase nuclei. Interestingly, all these alterations were exclusively somatic in nature substantiating normal fertility status of NBR exposed males. Though the actual mechanism is not known, we hypothesize that some putative innate protective mechanisms are operative in germline to counteract the effect of NBR. Analysis of additional Y linked loci may uncover the overall impact of NBR on the structural and functional attributes of this chromosome.
Persons with greater individual genome-wide heterozygosity show lower increase of cortisol levels during acute psychological stress
L. Zgaga1, C. Hayward2, Z. Biloglav1, I. Kolcic1, O. Polasek1,3, D. Rudan4, A. Vorko-Jovic1, A. Wright2, H. Campbell3, I. Rudan3;
1Medical School, University of Zagreb, Zagreb, Croatia, 2MRC Human Genetics Unit, Edinburgh, United Kingdom, 3Faculty of Medicine, Edinburgh, United Kingdom, 4Dubrava University Hospital, Zagreb, Croatia.
Presentation Number: P07.061
Aim: Genome-wide heterozygosity (GWH) was reported to affect a range of quantitative traits in humans, animals and plants. Several studies suggested that the underlying mechanism is increased compensation potential to environmental stressors in outbred individuals. In humans, psychological stress has been consistently linked to an increase in cortisol levels, which eventually impairs immune system function. We studied whether GWH status affects the increase in cortisol levels in persons reporting acute psychological stress.
Materials and methods: We studied 1,026 examinees from the Vis island, Croatia. Standardised multilocus heterozygosity (sMLH) was computed for each person from a genome-wide scan using 317.000 single nucleotide polymorphisms. Morning cortisol level was measured from the blood in all participants. Reported acute psychological stress was measured using General Health Questionnaire 30 (GHQ-30).
Results: GHQ-30 scores had a significant effect on the increase of cortisol (p<0.001). All examinees were therefore categorized in 3 groups according to the increasing levels of reported psychological stress within GHQ-30. In all groups, the effect of sMLH on cortisol levels was investigated using general linear model with inclusion of potential confounding variables. In the group reporting mild stress the effect was weak and non-significant (Beta=-0.058, p=0.34), but with increase of reported stress levels to moderate and strong, the effect became larger and statistically significant (Beta =-0.125, p=0.003; and Beta=-0.188, p=0.04, respectively).
Conclusion: This study implies that, in humans, the increase in individual GWH may buffer the effects of psychological stress on cortisol levels, thus protecting the physiological function of immune and endocrine system.
Comparison of genome-wide homozygosity-by-descent estimates in human isolated population
O. Polasek1,2, I. Kolc(ic'2, L. Zgaga2, Z. Biloglav2, A. Vorko Jovic'2, D. Rudan3, I. Rudan4, A. Wright5, H. Campbell1, A. Leutenegger6,7;
1Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom, 2Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia, 3Clinical Hospital Dubrava, Zagreb, Croatia, 4Centre for Global Health, University of Split, Split, Croatia, 5Human Genetics Unit, Medical Research Council, Edinburgh, United Kingdom, 6Inserm U535, Villejuif, France, 7Univ. Paris-Sud, Villejuif, France.
Presentation Number: P07.068
The aim of this study was to investigate several methods of marker based genome-wide homozygosity estimation. The study sample consisted of 118 members of a single extended family living on the Adriatic Croatian island of Vis, where no pedigree based inbreeding was observed, and therefore no homozygosity by descent, HBD, was expected. Individuals were genotyped for 810 microsatellite markers and a 317k Illumina chip. Five approaches were compared: the proportion of heterozygous loci (multilocus heterozygosity, MLH), two methods of moments approaches that use different weighting approaches (ADC and PLINK), and finally 2 maximum likelihood approaches, one singlepoint and the other multipoint, using a hidden Markov model for marker dependencies (FEstim). The latter is the only existing multipoint method for HBD estimation and gives estimates the closest to the true HBD values, as shown previously in a simulation study. The results indicated that the two methods of moments approaches correlated highly with MLH and hence did not bring much information about HBD. On the other hand, the two maximum likelihood approaches exhibited zero value estimates when homozygosity was likely due to chance. A total of 68 individuals (57.6%) had no HBD as defined by the FEstim, while a total of 4 individuals (3.9%) had FEstim values over 0.0625 indicating inbreeding closer than first cousins. These methods can be used to differentiate homozygosity by chance vs. HBD, which may be important in investigation of the genome-wide heterozygosity effects on quantitative and health related traits.
Genetic differentiation of ethnic groups of Russia evaluated by genes of hereditary disorders
R. A. Zinchenko, V. A. Galkina, E. K. Ginter;
Research Center for Medical Genetics, ??scow, Russian Federation.
Presentation Number: P07.057
On the basis of genetic epidemiological study the prevalence of autosomal dominant, autosomal recessive and X-linked recessive disorders in 10 regions of Russia (5 ethnic groups: Russians, Maris, Chuvashs, Udmurts, Adighes) was estimated. The size of the investigated population was more than 2.5 millions of persons. Genetic differentiation between populations of different hierarchical levels by estimated loads of hereditary diseases was established. The prevalence rate of all Mendelian disorders varied in the investigated populations from 1.34 to 5.92 per 1000 persons. Genetic diversity of hereditary diseases in the investigated populations was also under our study. 199 autosomal dominant, 165 autosomal recessive and 48 X-linked recessive diseases were revealed. Most of them were rare or very rare. There were some cases of local accumulations of hereditary disorders in the investigated populations. Simultaneously with medical genetic study the population genetic study was performed in the populations. By comparing both studies it was suggested that the genetic drift is a most important factor which determines genetic differentiation of populations by the prevalence and genetic diversity of autosomal disorders.
Genetic care of families affected by albinism in an African cultural context
P. M. Lund;
Coventry University, Coventry, United Kingdom.
Presentation Number: P09.47
The birth of a baby with the autosomal recessive condition oculocutaneous albinism (OCA) in a black African population is often traumatic for the mother as the phenotype, with hypopigmentation of the hair, skin and eyes, differs so visibly from the normal level of pigmentation in this group. The incidence of OCA among the Venda of northern South Africa is relatively high, with 1 in 1970 affected, giving a carrier rate of 1 in 23. Myth and superstition surround OCA, with affected families believing they have been bewitched. The experiences of genetic nurses at the large regional hospitals in Venda and of families who have benefited from their genetic counselling services are explored via semi structured interviews. The genetic nurses, based in the midwifery section, identify affected babies as part of the National Birth Surveillance Programme and intervene immediately to inform the mother of the special health care needs of her baby. They explain the genetic causes of OCA and aim to empower her to counter negative attitudes she is likely to encounter from her family, who may accuse her of infidelity, and the wider community when returning to her rural home. Barriers to the provision of genetic care in this remote, rural region and strategies adopted by health care professionals to overcome these difficulties are explored. This genetic practice is a model for providing care to those affected by genetic conditions in rural, low resources regions of the world.
MC1R polymorphisms, phenotype and UVB radiation sensitivity in melanoma risk patients
P. Aguilera1, C. Carrera1, G. Salerni1, F. Cuellar1, Z. Ogbah2, J. A. Puig-Butille2, M. Lecha3, J. Malvehy1, S. Puig1;
1Melanoma Unit, Barcelona, Spain, 2Melanoma Unit, Genetic Service, Barcelona, Spain, 3Photobiology and Phototherapy Unit, Dermatology Service, Barcelona, Spain.
Presentation Number: P04.161
Background: UV radiation (UVR) plays an important role in melanocytic tumours development. History of intense intermittent sun-exposure, phenotypic characteristics encoding melanocortin-1 receptor gene (MC1R) and the presence of multiple nevi are risk markers to develop malignant melanoma. Familiar melanoma represents 10% of all melanomas and it is supposed that genetic burden in these patients plays a more important role than environmental factors.
Objective: to study in different melanoma-risk patient settings the association between phenotypic characteristics, number of nevi, UVR sensitivity and polymorphisms in MC1R.
Methods: two groups of high risk melanoma patients were studied (N=32):
Group 1: Dysplastic nevus syndrome (DNS) patients (N=23).
Group 2: Melanoma patients belonging to familial melanoma (N=9).
UVB sensitivity, phenotypic and genotypic characterization were performed.
Results: patients from DNS had a higher UV-B photosensitivity (reduced UV-B minimal erythemal dose) compared with patients from familiar melanoma group (mean 88mJ/cm2± 26 vs 122 mJ/cm2 ± 26; p<0,005). In both groups a high percentage of MC1R polymorphisms were detected (at least 1 polymorphism in 75% of patients in group 1 vs 78% in group 2). However, a different percentage of red hair type polymorphisms (RHP) was observed in the 2 groups (20% in group 1 vs 66% in group 2, p<0,01).
Conclusions: Patients affected by DNS presented high UV-B sensitivity, similar to North European populations or patients with photo-dermatoses. Similar percentage of MC1R polymorphisms were detected in our both samples, however, RHPs were strongly associated with familial melanoma, an unexpected result in our Mediterranean area.
Super-hotspots for Meiotic Recombination in the Human Genome
Presentation Time: Tuesday, 11:00 a.m. - 11:15 a.m.
I. L. Berg, A. J. Webb, A. J. Jeffreys;
Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom.
Presentation Number: C13.2
Homologous recombination is a vital process for ensuring proper chromosome segregation during meiosis, as well as increasing diversity by reshuffling haplotypes between generations. In this study, we analysed Phase II HapMap data to identify autosomal regions showing extreme breakdown of linkage disequilibrium (LD). Sixteen of these regions were selected for crossover analysis directly in sperm. All contained active sperm hotspots, with similar characteristics as at previously studied hotspots, i.e. normally-distributed crossover breakpoints within regions 1-2 kb wide. These new hotspots were on average 10 fold more active than previously characterised autosomal hotspots and include the most active crossover hotspots yet discovered in the human genome. Their activity is however poorly predicted from LD data. Most crossovers in these hotspots were simple, exchanging haplotypes within a single interval between markers. However, 0.3% of exchanges were more complex, switching haplotypes at several intervals during an exchange event. Most of these occurred within the boundaries of the hotspot while 22% occurred beyond the hotpot, implying a broader region involved during intermediate stages of recombination. Several hotspots showed crossover frequency variation between men, including two cases of complete presence/absence polymorphism. Instances of extreme or subtle biased gene conversion accompanying crossover were observed within some hotspots, in some cases correlating with crossover frequency variation between men. Curiously none of the most active hotpots showed polymorphism or strongly biased conversion, in contrast to the prediction that these hotpots should be the most vulnerable to attenuation/extinction by meiotic drive in favour of recombination suppressors.
G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth
Presentation Time: Saturday, 7:00 p.m. - 7:15 p.m.
S. M. Pasternack1, I. von Kügelgen2, K. Al Aboud3, Y. Lee4,5, F. Rüschendorf5, K. Voss6, A. M. Hillmer7, G. J. Molderings2, T. Franz8, A. Ramirez9,10, P. Nürnberg10,11, M. M. Nöthen1,7, R. C. Betz1;
1Institute of Human Genetics, Bonn, Germany, 2Department of Pharmacology, Bonn, Germany, 3Department of Dermatology, Makkah, Saudi Arabia, 4Department of Pediatric Pneumology and Immunology, Berlin, Germany, 5Max Delbrück Center for Molecular Medicine, Berlin, Germany, 6Department of Human Genetics, Würzburg, Germany, 7Department of Genomics, Bonn, Germany, 8Department of Anatomy, Bonn, Germany, 9Institute of Human Genetics, Cologne, Germany, 10Center for Molecular Medicine Cologne, Cologne, Germany, 11Cologne Center for Genomics, Cologne, Germany.
Presentation Number: PL2.3
Hypotrichosis simplex (MIM 146520 and MIM 605389) is a group of hereditary non-syndromic human alopecias that affects men and women equally. The hair loss is diffuse and progressive, and usually begins in early childhood. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, a gene which encodes an orphan G protein-coupled receptor. We analysed expression-patterns of P2RY5 in various human and mouse tissues and performed western blot and immunofluorescence analyses to characterize the protein. Furthermore, we identified oleoyl-L-a-lysophosphatidic acid (LPA), a bioactive lipid, as being a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signalling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. As P2RY5 is expressed in human hair follicle cells, but LPA4 and LPA5 are not, a loss of P2Y5 function will not be compensated for, and will ultimately lead to pathological changes and hair loss.
Our study is the first to implicate a G protein-coupled receptor as being essential for and specific to the maintenance of human hair growth. With the functional characterization of the P2Y5 receptor, we identify the missing link which is required for the transmission of the LPA signal through the cell membrane in hair follicle cells. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans.
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