Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry

Abstract

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects Ϸ1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study metaanalysis was 2.4 ؋ 10 ؊6 . We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P Ϸ 10 ؊7 : 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR ‫؍‬ 1.19, P ‫؍‬ 1.8 ؋ 10 ؊7 ) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR ‫؍‬ 1.37, P ‫؍‬ 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.genetics ͉ genome-wide association study B ipolar disorder (BP) is characterized by dramatic mood changes, with individuals experiencing alternating episodes of depression and mania interspersed with periods of normal function. BP is chronic, severely disabling, and life-threatening, with increased risk of suicide and estimated lifetime prevalence of Ϸ1% (1).BP has a substantial genetic component. Monozygotic twin concordance rate estimates range from 45 to 70% and sibling recurrence risk estimates from 5 to 10 (2). Nonetheless, the underlying genetic and neurobiological triggers of BP remain elusive. Numerous linkage and candidate gene studies have sought to identify BP linked regions and associated genes, but no loci have been convincingly identified. Several groups have recently reported results of BP genome-wide association studies (GWAS), using pooled (3) or individually genotyped (4-6) samples; these studies identified SNPs in CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel), ANK3 (ankyrin 3), and DGKH (diacylglycerol kinase, eta) as potentially associated with BP.To test for SNP-BP association in additional well-characterized samples, we analyzed data for Ͼ2.3 million genotyped and imputed SNPs on Ͼ3,700 individuals in 2 sample sets: (i) 1,177 bipolar I ...

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