Erasmus University RotterdamGenetic Epidemiology · PhDNetherlands · Rotterdam
R. McQuillan, N. Eklund, N. Pirastu, M. Kuningas, B. P. McEvoy, T. Esko, T. Corre, G. Davies, M. Kaakinen, L. P. Lyytikainen, [......], D. Toniolo, J. G. Eriksson, A. Jula, O. T. Raitakari, A. Metspalu, M. Perola, M. R. Jarvelin, A. Uitterlinden, P. M. Visscher, J. F. Wilson[show abstract] [hide abstract]
ABSTRACT: Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (chi(2) = 83.89, df = 1; p = 5.2x10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.PLoS Genet. 01/2012; 8(7):e1002655.
Article: A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila.K V Allebrandt, N Amin, B Müller-Myhsok, T Esko, M Teder-Laving, R V D M Azevedo, C Hayward, J van Mill, N Vogelzangs, E W Green, [......], P P Pramstaller, Z Dogas, I Rudan, M Merrow, B Penninx, C P Kyriacou, A Metspalu, C M van Duijn, T Meitinger, T Roenneberg[show abstract] [hide abstract]
ABSTRACT: Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains ≈5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism.Molecular Psychiatry advance online publication, 22 November 2011; doi:10.1038/mp.2011.142.Molecular psychiatry 11/2011; · 15.05 Impact Factor
Article: The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association dataC M Middeldorp, M H M de Moor, L M McGrath, S D Gordon, D H Blackwood, P T Costa, A Terracciano, R F Krueger, E J C de Geus, D R Nyholt, [......], G R Abecasis, I J Deary, K R|[auml]|ikk|[ouml]|nen, L J Bierut, N G Martin, N R Wray, C M van Duijn, J W Smoller, B W J H Penninx, D I Boomsma[show abstract] [hide abstract]
ABSTRACT: The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case–Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ~0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.Keywords: bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depressionTranslational Psychiatry. 09/2011; 1(10):e50.
Article: Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.N Amin, E Byrne, J Johnson, G Chenevix-Trench, S Walter, I M Nolte, J M Vink, R Rawal, M Mangino, A Teumer, [......], H Tiemeier, B H R Wolfenbuttel, B A Oostra, A C Heath, E Wichmann, T D Spector, H J Grabe, D I Boomsma, N G Martin, C M van Duijn[show abstract] [hide abstract]
ABSTRACT: Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).Molecular psychiatry 08/2011; 17(11):1116-29. · 15.05 Impact Factor
N Amin, M Schuur, E S Gusareva, A Isaacs, Y S Aulchenko, A V Kirichenko, I V Zorkoltseva, T I Axenovich, B A Oostra, A C J W Janssens, C M van Duijn[show abstract] [hide abstract]
ABSTRACT: The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)=5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values=0.009, 0.007), in 17q24 for agreeableness (marginal P-value=0.018) and in 20p13 for conscientiousness (marginal P-values=0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques.Molecular psychiatry 08/2011; 17(10):1031-41. · 15.05 Impact Factor