What is amazing to me is that these same geneticists embrace hypotheses of population history that cannot possibly have happened. The other geneticists quoted in the article, Carlos Bustamante and his graduate student Kirk Lohmueller, wrote a paper earlier this spring arguing that deleterious mutations have reached high frequency in Europeans (moreso than Africans) because of a bottleneck during European history. The press reported this work as "Whites genetically weaker than blacks, study finds." The hypothesis in the paper is that protein-coding sites otherwise conserved in most mammals may differ among humans because of relaxed selection in a bottleneck.
Here's why they're wrong: their bottleneck is impossible. They propose that the European population was a small, isolated population of 5,700 effective individuals from 214,000 years ago up to the Last Glacial Maximum. I suppose I should take some encouragement that they believe Neandertals were European ancestors (because otherwise, where exactly would this small, isolated population of Europeans have lived). But it's still quite impossible -- it implies no gene flow between Africans and Europeans across that entire span. You see, that is the only way that genetic drift can lead to this kind of result -- large differences in frequencies between continents for hundreds of deleterious alleles. It takes a bottleneck of exceptional length, along with complete isolation.
In what has become a troubling trend, these details were hidden away in the online supplementary information of the paper. It is no surprise that most people read only the paper's conclusions, without critically evaluating the methods. But when the assumptions are hidden so that it takes an effort to look at them, you can understand that the paper does not receive the kind of scrutiny that it deserves. These are not obscure laboratory techniques; they are the basic evidence on which the conclusions were based.
Now, Bustamante knows that positive selection has been very important in recent human evolution, because he wrote an important paper on the subject in 2005. I wrote about the paper at the time -- it was one of the works that really got us thinking about acceleration in the first place. So why in the world did their more recent paper adopt such a ridiculous model of population history?
In any event, I don't think that either of these studies from earlier this year are relevant to our acceleration results. They address different aspects of genetic variation. However, acceleration may help to explain the high frequencies of some gene variants conserved in other mammals -- the results explained by Lohmueller and colleagues as relaxed selection under a bottleneck.
The acceleration of recent positive selection would predict that many otherwise conserved gene variants may be segregating in humans, because they are the targets of positive selection. These conserved sites are among those most likely to show a strong sign of recent selection, because adaptive changes on them are necessarily rare (we know they're rare, because they haven't happened very often among other species). Most such sites are still conserved in humans -- it's just not possible to change their function in adaptive ways. But the massive ecological changes of recent human history have created the opportunity for adaptive responses that are not present in other mammalian lineages. We shouldn't be surprised to see that some such changes are currently underway.
Europeans more highly evolved, not "genetically weaker"
This part of John Hawks' most recent post is worth pointing out:
Kin selection and the evolution of virulence
Heredity (2008) 100, 484–488; doi:10.1038/sj.hdy.6801093; published online 23 January 2008
Kin selection and the evolution of virulence (pdf)
A Buckling and M A Brockhurst
Social interactions between conspecific parasites are partly dependent on the relatedness of interacting parasites (kin selection), which, in turn, is predicted to affect the extent of damage they cause their hosts (virulence). High relatedness is generally assumed to favour less competitive interactions, but the relationship between relatedness and virulence is crucially dependent on the social behaviour in question. Here, we discuss the rather limited body of experimental work that addresses how kin-selected social behaviours affect virulence. First, if prudent use of host resources (a form of cooperation) maximizes the transmission success of the parasite population, decreased relatedness is predicted to result in increased host exploitation and virulence. Experimental support for this well-established theoretical result is surprisingly limited. Second, if parasite within-host growth rate is a positive function of cooperation (that is, when individuals need to donate public goods, such as extracellular enzymes), virulence is predicted to increase with increasing relatedness. The limited studies testing this hypothesis are broadly consistent with this prediction. Finally, there is some empirical evidence supporting theory that suggests that spiteful behaviours are maximized at intermediate degrees of relatedness, which, in turn, leads to minimal virulence because of the reduced growth rate of the infecting population. We highlight the need for further thorough experimentation on the role of kin selection in the evolution of virulence and identify additional biological complexities to these simple frameworks.
Keywords: experimental evolution, parasite, cooperation, spite, microbe, public goods
Kin selection and the evolution of virulence (pdf)
A Buckling and M A Brockhurst
Social interactions between conspecific parasites are partly dependent on the relatedness of interacting parasites (kin selection), which, in turn, is predicted to affect the extent of damage they cause their hosts (virulence). High relatedness is generally assumed to favour less competitive interactions, but the relationship between relatedness and virulence is crucially dependent on the social behaviour in question. Here, we discuss the rather limited body of experimental work that addresses how kin-selected social behaviours affect virulence. First, if prudent use of host resources (a form of cooperation) maximizes the transmission success of the parasite population, decreased relatedness is predicted to result in increased host exploitation and virulence. Experimental support for this well-established theoretical result is surprisingly limited. Second, if parasite within-host growth rate is a positive function of cooperation (that is, when individuals need to donate public goods, such as extracellular enzymes), virulence is predicted to increase with increasing relatedness. The limited studies testing this hypothesis are broadly consistent with this prediction. Finally, there is some empirical evidence supporting theory that suggests that spiteful behaviours are maximized at intermediate degrees of relatedness, which, in turn, leads to minimal virulence because of the reduced growth rate of the infecting population. We highlight the need for further thorough experimentation on the role of kin selection in the evolution of virulence and identify additional biological complexities to these simple frameworks.
Keywords: experimental evolution, parasite, cooperation, spite, microbe, public goods
Ancient Japan: Jomon vs. Yayoi limb proportions
American Journal of Physical Anthropology; 10.1002/ajpa.20853; Published Online: 16 May 2008
Variation in limb proportions between Jomon foragers and Yayoi agriculturalists from prehistoric Japan
Daniel H. Temple et al.
Keywords: ecogeography, canalization, phenotypic plasticity, Allen's rule, migration
Variation in limb proportions between prehistoric Jomon and Yayoi people of Japan are explored by this study. Jomon people were the descendents of Pleistocene nomads who migrated to the Japanese Islands around 30,000 yBP. Phenotypic and genotypic evidence indicates that Yayoi people were recent migrants to Japan from continental Northeast Asia who likely interbred with Jomon foragers. Limb proportions of Jomon and Yayoi people were compared using RMA regression and Quick-Test calculations to investigate relative variability between these two groups. Cluster and principal components analyses were performed on size-standardized limb lengths and used to compare Jomon and Yayoi people with other groups from various climatic zones. Elongated distal relative to proximal limb lengths were observed among Jomon compared to Yayoi people. Jomon limb proportions were similar to human groups from temperate/tropical climates at lower latitudes, while Yayoi limb proportions more closely resemble groups from colder climates at higher latitudes. Limb proportional similarities with groups from warmer environments among Jomon foragers likely reflect morphological changes following Pleistocene colonization of the Japanese Islands. Cold-derived limb proportions among the Yayoi people likely indicate retention of these traits following comparatively recent migrations to the Japanese Islands. Changes in limb proportions experienced by Jomon foragers and retention of cold-derived limb proportions among Yayoi people conform to previous findings that report changes in these proportions following long-standing evolution in a specific environment. Am J Phys Anthropol, 2008. © 2008 Wiley-Liss, Inc.
Variation in limb proportions between Jomon foragers and Yayoi agriculturalists from prehistoric Japan
Daniel H. Temple et al.
Keywords: ecogeography, canalization, phenotypic plasticity, Allen's rule, migration
Variation in limb proportions between prehistoric Jomon and Yayoi people of Japan are explored by this study. Jomon people were the descendents of Pleistocene nomads who migrated to the Japanese Islands around 30,000 yBP. Phenotypic and genotypic evidence indicates that Yayoi people were recent migrants to Japan from continental Northeast Asia who likely interbred with Jomon foragers. Limb proportions of Jomon and Yayoi people were compared using RMA regression and Quick-Test calculations to investigate relative variability between these two groups. Cluster and principal components analyses were performed on size-standardized limb lengths and used to compare Jomon and Yayoi people with other groups from various climatic zones. Elongated distal relative to proximal limb lengths were observed among Jomon compared to Yayoi people. Jomon limb proportions were similar to human groups from temperate/tropical climates at lower latitudes, while Yayoi limb proportions more closely resemble groups from colder climates at higher latitudes. Limb proportional similarities with groups from warmer environments among Jomon foragers likely reflect morphological changes following Pleistocene colonization of the Japanese Islands. Cold-derived limb proportions among the Yayoi people likely indicate retention of these traits following comparatively recent migrations to the Japanese Islands. Changes in limb proportions experienced by Jomon foragers and retention of cold-derived limb proportions among Yayoi people conform to previous findings that report changes in these proportions following long-standing evolution in a specific environment. Am J Phys Anthropol, 2008. © 2008 Wiley-Liss, Inc.
Ancient Britons "had geometry skills to rival Pythagoras"
The Independent reports:
(via rogueclassicism)
Stone Age Britons had a sophisticated knowledge of geometry to rival Pythagoras – 2,000 years before the Greek "father of numbers" was born, according to a new study of Stonehenge.
Five years of detailed research, carried out by the Oxford University landscape archaeologist Anthony Johnson, claims that Stonehenge was designed and built using advanced geometry.
The discovery has immense implications for understanding the monument – and the people who built it. It also suggests it is more rooted in the study of geometry than early astronomy – as is often speculated.
Mr Johnson believes the geometrical knowledge eventually used to plan, pre-fabricate and erect Stonehenge was learnt empirically hundreds of years earlier through the construction of much simpler monuments.
[. . .]
The experimental archaeology demonstrates that most of the monument was pre-planned and that the great stones were pre-fabricated off-site and then installed by surveyor-engineers.
"For years people have speculated that Stonehenge was built as a complex astronomical observatory. My research suggests that, apart from mid-summer and mid-winter solar alignments, this was not the case," said Mr Johnson. "It strongly suggests that it was the knowledge of geometry and symmetry which was an important component of the Neolithic belief system."
"It shows the builders of Stonehenge had a sophisticated yet empirically derived knowledge of Pythagorean geometry 2000 years before Pythagoras," he said.
(via rogueclassicism)
Human population history: a reconstruction based on HGDP genome-wide SNP data
From the press release:
Sounds interesting, but no doubt far from definitive looking at only 2540 SNPs and a limited number of populations.
Finns were not included in the analysis, but this independent evidence of west-east gene flow in northern Eurasia is in line with the theory that N3 (Tat C) Y chromosomes diffused from Northeastern Europeans to Siberians rather than the reverse:
'Our technique enables us to identify more subtle details about genetic contributions than other methods,' said Dr Garrett Hellenthal from the Department of Statistics at Oxford, a co-author on the paper. 'By incorporating the inheritance of 'blocks' of DNA between generations, rather than just individual genes, it captures a panoramic view of the sharing of patterns of DNA across the entire human genome. This allows us to consider a vast number of possible colonisation scenarios - not just the ones people have already thought of - and use an algorithm to determine the most likely migration routes.'
The new technique was used to analyse 2540 genetic markers using Single Nucleotide Polymorphism data from 927 individuals of diverse ethnicity whose DNA was collected by the Human Diversity Project.
'Humans like to tell stories and amongst the most captivating is the story of the global spread of modern humans from their original homeland in Africa,' said Dr Daniel Falush of University College Cork, a co-author on the paper. 'Traditionally this has been the preserve of anthropologists but geneticists are now starting to make an important contribution. However, genetic evidence is still typically analysed in the light of anthropological preconceptions; statistical techniques help us to see things more objectively.'
The researchers believe their method can cope with much larger datasets with over 500,000 genetic markers. Further developments of the technique should allow human ancestry to be reconstructed in unprecedented detail and give a perspective independent of anthropological theory and interpretation.
Sounds interesting, but no doubt far from definitive looking at only 2540 SNPs and a limited number of populations.
PLoS Genet 4(5): e1000078. doi:10.1371/journal.pgen.1000078
Inferring Human Colonization History Using a Copying Model
Garrett Hellenthal et al.
Genome-wide scans of genetic variation can potentially provide detailed information on how modern humans colonized the world but require new methods of analysis. We introduce a statistical approach that uses Single Nucleotide Polymorphism (SNP) data to identify sharing of chromosomal segments between populations and uses the pattern of sharing to reconstruct a detailed colonization scenario. We apply our model to the SNP data for the 53 populations of the Human Genome Diversity Project described in Conrad et al. (Nature Genetics 38,1251-60, 2006). Our results are consistent with the consensus view of a single “Out-of-Africa” bottleneck and serial dilution of diversity during global colonization, including a prominent East Asian bottleneck. They also suggest novel details including: (1) the most northerly East Asian population in the sample (Yakut) has received a significant genetic contribution from the ancestors of the most northerly European one (Orcadian). (2) Native South Americans have received ancestry from a source closely related to modern North-East Asians (Mongolians and Oroquen) that is distinct from the sources for native North Americans, implying multiple waves of migration into the Americas. A detailed depiction of the peopling of the world is available in animated form.
[. . .]
Gene Flow from Europe to East Asia around the Arctic Circle
In our inferred scenario there is little gene flow between East Asian and Europeans and the Yakut is the only East Asian population to have two European donors; the Russians and the Orcadians. The Russian contribution is not surprising because the Yakut live in North East Russia. The Orcadian contribution is particularly noteworthy because removing these donors reduces the log-likelihood of generating the Yakut chromosomes by 2.5 times more than removing donors from any other population (Table S2). The Orcadians are also the only other European population to donate to other East Asians, namely the Han from Northern China and the Hezhen, who are also amongst the most Northerly East Asian populations in the sample. On this basis we hypothesize that there has been an episode of gene flow from Europe to East Asia. We tested the robustness of this inference by putting Orcadians last in the ordering. The Yakut replaced the Orcadians with Sardinians, who are a major donor to the Orcadians. The Hezhen and the Han from Northern China did not acquire new European donors, consistent with the gene flow from Europe being less quantitatively important to these two populations than to the more Northerly Yakut. Orcadians did not gain any East Asian donors by being placed last in the ordering, strengthening the inference that the direction of the gene flow was from Europe to East Asia.
Finns were not included in the analysis, but this independent evidence of west-east gene flow in northern Eurasia is in line with the theory that N3 (Tat C) Y chromosomes diffused from Northeastern Europeans to Siberians rather than the reverse:
The peculiar Y chromosomal DNA variant, known as Tat C, is also dominant in almost all the indigenous peoples of Siberia, from the nomadic Yakuts right across to the Chukchis and Siberian Inuits living on the shores of the Bering Strait - regardless of what language they may communicate in.
According to Prof. Villems, the "point" in all this is that among the Finno-Ugric races of Europe this genetic inheritance is much more diverse, more multibranched, and hence apparently older than among any of the Siberian peoples.
Height (ESHG 2008 abstracts)
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.
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.
2008-05-26 links
Statistical Modeling, Causal Inference, and Social Science: Voting patterns of Jews and other religious groups; Quarterbacks and psychometrics
Studium generale: Die Hausmaus in der Weltgeschichte
Mathilda's Anthropology Blog: The domestication and ancient pedigree of the housecat
Plomin et al.: Testing replication of a 5-SNP set for general cognitive ability in six population samples
mtDNA and disease: no association between the common [mitochondrial DNA haplogroups] and prostate cancer in the Korean population
AJPA: Middle Eastern and European mtDNA lineages characterize populations from eastern Crete
Studium generale: Die Hausmaus in der Weltgeschichte
Mathilda's Anthropology Blog: The domestication and ancient pedigree of the housecat
Plomin et al.: Testing replication of a 5-SNP set for general cognitive ability in six population samples
mtDNA and disease: no association between the common [mitochondrial DNA haplogroups] and prostate cancer in the Korean population
AJPA: Middle Eastern and European mtDNA lineages characterize populations from eastern Crete
Positive selection at MC1R in Europeans?
BMC Genetics 2008, 9:31doi:10.1186/1471-2156-9-31
Nucleotide diversity and population differentiation of the Melanocortin 1 Receptor gene, MC1R
Sharon A Savage et al.
Background
The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk.
Results
Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, ?, was much higher (10.1 × 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe.
Conclusion
This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R.
[. . .]
Numerous studies have demonstrated associations between specific MC1R variants and red hair, light skin, poor tanning ability and heavy freckling [4-9]. A recent genome-wide association scan confirmed the role of MC1R SNPs in hair, eye, and skin pigmentation[3]. The functional role of many of these variants has been described [10-13]. Several MC1R variants are also associated with increased risk of malignant melanoma in a variety of populations [14-22] The effect of MC1R polymorphisms in melanoma risk appears to extend beyond its effect on pigmentation in most of these investigations, and to be linked to melanomas harboring mutations in the BRAF oncogene[23].
Several hypotheses have been generated in an effort to understand the evolutionary history of skin pigmentation in humans. It has been suggested that as humans migrated out of Africa to climates with more limited exposure to sunlight, relaxation of functional constraints in pigmentation genes, including MC1R, or selection for functionally relevant variants that led to lighter skin pigmentation occurred[24]. This could result in an improved ability to synthesize vitamin D in the presence of limited sunlight exposures [25-27]. It has also been suggested that darker skin is favored in regions closer to the equator for protection against ultraviolet radiation[24]. In addition, differences in skin pigmentation could protect against pathogens and cold injury, and may have also been important in sexual selection[28].
[. . . ]
Several studies have evaluated genetic adaptation of the MC1R gene for evidence of positive selection with conflicting results. Some studies suggested that purifying selection is present in Africa and that relaxation of functional constraint in non-African populations, instead of positive selection, is present[25,27,40]. On the other hand, most recent studies have found evidence of positive selection at other pigmentation genes. For example, Myles et al [2] found evidence for positive selection in the DCT gene among individuals of Chinese ancestry. In their study, MC1R interpretations were limited because of the different SNPs genotyped between the Perlegen and HapMap data sets studied. In a study of 118 putative skin pigmentation genes, data were consistent with positive selection in subjects from Europe (OCA2, TYRP1, and KITLG) and in Asians (DCT, EGFR, and DRD2)[38]. Unfortunately, MC1R could not be evaluated in that study due to ascertainment criteria. It was also suggested that at least weak, recent positive selection may be present in MC1R, based on the AF variability between CEPH Utah and East Asian HapMap samples[3]. Our data suggest that MC1R may be under positive selection in some populations, although additional studies are needed to further evaluate this finding.
Nucleotide diversity and population differentiation of the Melanocortin 1 Receptor gene, MC1R
Sharon A Savage et al.
Background
The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk.
Results
Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, ?, was much higher (10.1 × 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe.
Conclusion
This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R.
[. . .]
Numerous studies have demonstrated associations between specific MC1R variants and red hair, light skin, poor tanning ability and heavy freckling [4-9]. A recent genome-wide association scan confirmed the role of MC1R SNPs in hair, eye, and skin pigmentation[3]. The functional role of many of these variants has been described [10-13]. Several MC1R variants are also associated with increased risk of malignant melanoma in a variety of populations [14-22] The effect of MC1R polymorphisms in melanoma risk appears to extend beyond its effect on pigmentation in most of these investigations, and to be linked to melanomas harboring mutations in the BRAF oncogene[23].
Several hypotheses have been generated in an effort to understand the evolutionary history of skin pigmentation in humans. It has been suggested that as humans migrated out of Africa to climates with more limited exposure to sunlight, relaxation of functional constraints in pigmentation genes, including MC1R, or selection for functionally relevant variants that led to lighter skin pigmentation occurred[24]. This could result in an improved ability to synthesize vitamin D in the presence of limited sunlight exposures [25-27]. It has also been suggested that darker skin is favored in regions closer to the equator for protection against ultraviolet radiation[24]. In addition, differences in skin pigmentation could protect against pathogens and cold injury, and may have also been important in sexual selection[28].
[. . . ]
Several studies have evaluated genetic adaptation of the MC1R gene for evidence of positive selection with conflicting results. Some studies suggested that purifying selection is present in Africa and that relaxation of functional constraint in non-African populations, instead of positive selection, is present[25,27,40]. On the other hand, most recent studies have found evidence of positive selection at other pigmentation genes. For example, Myles et al [2] found evidence for positive selection in the DCT gene among individuals of Chinese ancestry. In their study, MC1R interpretations were limited because of the different SNPs genotyped between the Perlegen and HapMap data sets studied. In a study of 118 putative skin pigmentation genes, data were consistent with positive selection in subjects from Europe (OCA2, TYRP1, and KITLG) and in Asians (DCT, EGFR, and DRD2)[38]. Unfortunately, MC1R could not be evaluated in that study due to ascertainment criteria. It was also suggested that at least weak, recent positive selection may be present in MC1R, based on the AF variability between CEPH Utah and East Asian HapMap samples[3]. Our data suggest that MC1R may be under positive selection in some populations, although additional studies are needed to further evaluate this finding.
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.
A Saami admixture estimate
As always, I tend to be skeptical about the utility of HLA for accurately determining population affinities.
European Journal of Human Genetics advance online publication 14 May 2008; doi: 10.1038/ejhg.2008.88
Genetic origin of the Swedish Sami inferred from HLA class I and class II allele frequencies
Åsa Johansson et al.
Sami of northern Scandinavia are genetic outliers among European populations and their origin has been difficult to determine. In order to study the genetic origin of the Swedish Sami, we have performed high-resolution typing of the class I HLA-A and -B loci and the class II DRB1, DQB1 and DQA1 loci in the northern and southern Swedish Sami. Several of the common class I alleles in Sami (B*0702, B*1501, B*4002 and A*0301) are found at high frequency in other European populations. However, a number of class I and class II alleles (B*4001, A*2402, DRB1*0901 and DRB1*1101) in the Swedish Sami are characteristic of Asian populations. Admixture analyses indicate that 87% of the Sami gene pool is of European origin and that the Asian contribution is 13%. Our HLA analyses indicate a higher proportion of Asian ancestry in the Sami than shown by previous genetic studies.
Keywords: Sami, HLA, genetic origin, admixture
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.
Genetic variation in India
Some recent papers from the open-access International Journal of Human Genetics.
The quality of submissions published in this journals seems to be highly variable. I know I'll be waiting with bated breath for this forthcoming paper:
Int J Hum Genet, 8(1-2): 21-29 (2008)
The Grandest Genetic Experiment Ever Performed on Man? A Y-Chromosomal Perspective on Genetic Variation in India (pdf )
Denise R. Carvalho-Silva and Chris Tyler-Smith
KEYWORDS Y chromosome; genetic variation; Indian caste system; endogamy; population substructure
We have analysed Y-chromosomal data from Indian caste, Indian tribal and East Asian populations in order to investigate the impact of the caste system on male genetic variation. We find that variation within populations is lower in India than in East Asia, while variation between populations is overall higher. This observation can be explained by greater subdivision within the Indian population, leading to more genetic drift. However, the effect is most marked in the tribal populations, and the level of variation between caste populations is similar to the level between Chinese populations. The caste system has therefore had a detectable impact on Y-chromosomal variation, but this has been less strong than the influence of the tribal system, perhaps because of larger population sizes in the castes, more gene flow or a shorter period of time.
Int J Hum Genet, 8(1-2): 41-50 (2008)
Language Shift by Indigenous Population: A Model Genetic Study in South Asia (pdf)
Gyaneshwer Chaubey, Mait Metspalu, Monika Karmin, Kumarasamy Thangaraj, Siiri Rootsi, Juri Parik, Anu Solnik, Deepa Selvi Rani, Vijay Kumar Singh, B. Prathap Naidu, Alla G. Reddy, Ene Metspalu1, Lalji Singh, Toomas Kivisild and Richard Villems
KEYWORDS Mushar; language shift; mtDNA; Y-chromosome
Language shift is a phenomenon where a new language is adopted by a population with virtually no influence on its genetic makeup. We report here the results of a case study, carried out on the Mushar populations, which is thought to have undergone language shift from Munda (an Austro-Asiatic language) to Hindi (an Indo- European language). We compared the mtDNA and Y-chromosomal phylogenies of this population with those of the neighbouring Indo-European and Austro-Asiatic speaking populations, standing at similar social status. The results revealed much closer genetic affinity of the Mushar people to the neighbouring Austro-Asiatic (Mundari) populations, than to the neighbouring Hindi-speaking populations. This example shows that the language shift as such is not necessarily a signal for a rapid genetic admixture, either maternally or paternally.
Int J Hum Genet, 8(1-2): 31-39 (2008)
Molecular Genetic Study on the Status of Transitional Groups of Central India: Cultural Diffusion or Demic Diffusion? (pdf)
Vikrant Kumar et al.
KEYWORDS Genetic status; Dravidians; Indo-Europeans; Austro-Asiatics; Central India
Two different models of diffusion - demic and cultural - have been proposed as an explanation for the spread of languages. Recent studies have shown that in some cases the dispersal of the language was due to the demic diffusion while for others it is purely due to the process of acculturation. There are four major linguistic families in India which have largely their own geographic domain. However, there are a few situations in which the populations affiliated to different linguistic families cohabit. For example, we find the spread of the Indo-European and Dravidian tribal populations in the core/peripheral areas of the Mundari Austro-Asiatic groups. These non-Mundari groups have been termed as transitional populations to indicate that these populations originally were probably Mundaris. However, there has been no attempt to ascertain if these populations are genetically Austro-Asiatics or do they belong to the linguistic groups that they are currently affiliated to. To examine this we have analysed Y-SNPs and STRs data of the 13 Mundari and 7 transitional groups and compared with the other populations of relevant linguistic groups. The results suggest that the Indo-European transitional groups are genetically Mundari and have acquired the present language through the process of cultural diffusion, while in the case of Dravidian transitional groups, the spread of language seems to be due to the process of both, the demic and cultural diffusion.
Int J Hum Genet, 8(1-2): 97-118 (2008)
Genetic Imprints of Pleistocene Origin of Indian Populations: A Comprehensive Phylogeographic Sketch of Indian Y-Chromosomes (pdf)
R. Trivedi et al.
KEYWORDS Population genetics, people of india, linguistic groups, migration
Paleoanthropological evidence indicates that modern humans reached South Asia in one of the first dispersals out of Africa, which were later followed by migrations from different parts of the world. The variation of 20 microsatellite and 38 binary polymorphisms on the non-recombining part of the uniparental, hapliod Y-chromosome was examined in 1434 male individual of 87 different populations of India to investigate various hypothesis of migration and peopling of South Asia Sub-continent. This study revealed a total of 24 paternal lineages, of which haplogroups H, R1a1, O2a and R2 portrayed for approximately 70% of the Indian Y-Chromosomes. The high NRY diversity value (0.893) and coalescence age of approx. 45-50 KYA for H and C haplogroups signified an early settlement of the subcontinent by modern humans. Haplogroup frequency and AMOVA results provide similar evidence in support of a common Pleistocene origin of Indian populations, with partial influence of Indo-European gene pool on the Indian society. The differential Y-chromosome and mt DNA pattern in the two Austric speakers of India signaled that an earlier male–mediated exodus from South East Asia largely involved the Austro-Asiatic tribes, while the Tibeto-Burman males migrated with females through two different routes; one from Burma most likely brought the Naga-Kuki-Chin language and O3e Y-chromosomes and the other from Himalayas, which carried the YAP lineages into northern regions of subcontinent. Based on distribution of Y-chromosome haplogroups (H, C, O2a, and R2) and deep coalescing time depths for these paternal lineages, we propose that the present day Dravidian speaking populations of South India are the descendants of earliest Pleistocene settlers while Austro-Asiatic speakers came from SE Asia in a later migration event.
Int J Hum Genet, 8(1-2): 1-20 (2008)
Trends in Molecular Anthropological Studies in India (pdf)
Vikal Tripathy et al.
KEYWORDS Population structure; molecular anthropology; mtDNA; Y-chromosome; autosomal DNA; India
Indian population is characterized by wide diversity and unique population structure shaped by different waves of migration and the practice of caste endogamy. Anthropologists have been studying the peopling of India and the relationships between different populations using traditional genetic markers. With the advent of molecular genetic techniques the focus has turned to using the DNA polymorphisms for resolving different anthropological questions and to test the different hypotheses in vogue. In this paper we make an attempt to critically review the trends in molecular anthropological studies till date and bring out salient features of the findings. An attempt has been made to evaluate the merit of the molecular studies in the perspective of unique population structure of India.
The quality of submissions published in this journals seems to be highly variable. I know I'll be waiting with bated breath for this forthcoming paper:
REF. NO. IJHG-362
ACCEPTED
Origin and Spread of Dravidian Speakers
Clyde Winters
Uthman dan Fodio Institute, Chicago, Illinois 60643, USA
E-mail: c-winters@govst.edu
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.
2008-05-23 links
Intelligence and class: Social class IQ differences and university access (via Sailer)
Personal genomics: How To Use SNPedia for 23andMe and deCODEme
Basic statistics: Error bars in experimental biology (via bayblab)
Personal genomics: How To Use SNPedia for 23andMe and deCODEme
Basic statistics: Error bars in experimental biology (via bayblab)
2008-05-22 links
Sequencing technology: An innnovative approach could target hard-to-sequence areas
Genealogy: Ancestry.com makes military collection freely available May 20 through May 31; LDS's FamilySearch Record Search pilot site is now available without registering (1900 Census, etc.)
1924 Virginia Racial Integrity Act: Pointing and sputtering
Genetic Future: 23andMe, deCODEme and Navigenics at Cold Spring Harbor
Vestigial organs: Five things humans no longer need
Executive Function: Almost Perfectly Heritable
Schiller: Skull not his
ZS Genetics is a relative newcomer to the field and uses an approach vastly different than any other: electron microscopy. Glover predicts that by next year, the company's technology will be able to generate readable lengths of DNA that are thousands of base pairs long, and he believes that ZS Genetics' sequencing method will improve by a factor of 10 in the next couple of years, making the pieces even easier to assemble. The company was recently accepted as one of the teams in the Archon X Prize for Genomics, a $10 million award for the first privately funded team that can sequence 100 human genomes in 10 days.
Genealogy: Ancestry.com makes military collection freely available May 20 through May 31; LDS's FamilySearch Record Search pilot site is now available without registering (1900 Census, etc.)
1924 Virginia Racial Integrity Act: Pointing and sputtering
Genetic Future: 23andMe, deCODEme and Navigenics at Cold Spring Harbor
Vestigial organs: Five things humans no longer need
Executive Function: Almost Perfectly Heritable
Schiller: Skull not his
Schiller's remains had been interred in a mausoleum in Weimar's Jacobs cemetery that the state kept for distinguished citizens. But the remains were mixed with others, and when a total of 23 skulls were found, the city's mayor, Carl Leberecht Schwabe — a Schiller fan — declared that the biggest must have been that of the philosophic writer.
A skeleton believed to match the skull was then put together with it, and both were buried in 1827 in the city's Fuerstengruft cemetery. Germany's most revered writer, Johann Wolfgang von Goethe — who was Schiller's friend — was buried in a crypt alongside him in 1832 and today the site is visited by some 60,000 people per year.
But in 1911, Schiller researcher August von Froriep unearthed another skull that he said was that of the writer, and later claims emerged about still another skull.
According to the DNA results, however, none of the skulls were matches, MDR reported. The researchers used comparison samples taken from the remains of two of Schiller's sisters and two of his sons.
The results showed that the original Schiller skull belonged to an unidentified person, and that the "matching" skeleton was actually the bones of several other unidentified people, MDR reported.
The other two skulls also did not match, raising a new question: Where's Schiller?
Seemann said he thinks that the remains must still be in the original Jacobs cemetery — but added that his organization would not be taking part in any new search for them.
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.
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