A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P= 6.4x10(-9)), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest= 5.8x10(-10)), and supported three regions previously implicated in BD susceptibility: MAD1L1 (P-best= 1.9x10(-9)), TRANK1 (Pbest= 2.1x10(-9)) and ODZ4 (Pbest= 3.3x10(-9)). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', P-best similar to 10-29, R-2 similar to 2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' P-best similar to 10(-13), R-2 similar to 0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates similar to 0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.