Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

Abstract

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

“…This finding has been replicated in many (if not all) GWASs of bipolar disorder (3)(4)(5). The ANK3 locus is also found to be associated, to a lesser extent, with schizophrenia (6,7).…”

Genome-wide association study reveals two new risk loci for bipolar disorder

“…rs9834970, a SNP in low LD (r 2 ¼ 0.13, P GC ¼ 4.81 Â 10 À 8 , OR ¼ 1.12), had already reached genome-wide significance in a GWAS of BD by Chen et al 9 , which partially overlaps with the included PGC data. Analysis of rs9834970-C in MooDS showed P GC ¼ 0.0014 (OR ¼ 1.15), providing independent evidence for replication.…”

“…The MooDS-PGC GWAS revealed 56 SNPs reaching genomewide significance at five genomic loci, three of which had been described before (ANK3, ODZ4 and TRANK1) 4,9 . A subset of 18 non-correlated top SNPs, which were selected by a pruning on pairwise linkage disequilibrium (LD) between the associated SNPs, is provided in Table 2.…”

“…Motivated by this and the successes of GWAS for non-psychiatric phenotypes, a big step forward was taken through a recent large BD GWAS by the multi-national Psychiatric Genomics Consortium Bipolar Disorder Working Group (PGC-BD) 7 . We have previously published a GWAS of BD using a German sample (named Germany I) 8 that was thereafter included in the GWAS of the PGC-BD 7 and another subsequent BD GWAS 9 .…”

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…There is little clear evidence regarding ethnic‐specific locus‐heterogeneity, partly due to the smaller sample sizes currently available for non‐European gene discovery studies. However, a recent meta‐analysis of European and Asian GWAS data has shown that Asian subjects tend to have the same direction of effect for the most significantly associated loci ( P  < 1e‐06) with only ∼2% of the top 41 SNPs showing a different direction of effect to the European samples [Chen et al, 2013]. Additional method development to address the use of polygene scores in the presence of ethnic differences would be useful.…”