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.
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