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

Abstract

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=6.4 × 10−9), 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=5.8 × 10−10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10−9), TRANK1 (Pbest=2.1 × 10−9) and ODZ4 (Pbest=3.3 × 10−9). 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’, Pbest~10−29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for ‘trans-European-Japanese comparison,’ Pbest~10−13, R2~0.27%). This ‘trans population’ effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~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.

Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

“…In addition to our Chinese sample, we also collected the statistical data (OR and p value) of rs1064395 from two independent Japanese samples (Japan 01: 1,545 cases and 7,408 controls; Japan 02: 1,419 cases and 54,479 controls) [20] and six European datasets (MooDS GWAS, PGC1 GWAS, Iceland, France, Bosnia and Herzegovina/Serbia, and Romania) from previously published studies [13, 17, 18, 31]. The PGC1 GWAS statistical results were obtained from the Psychiatric Genomics Consortium public website (https://www.med.unc.edu/pgc).…”

Cardiolipin is essential for early embryonic viability and mitochondrial integrity of neurons in mammals

“…28 These conform to the well-known calcium dysregulation hypothesis of bipolar disorder 55 and also the mitochondrial dysfunction hypothesis. 57,58 Because fatty acid composition of CL in the brain is unique in particular, 59 further detailed F I G U R E 8 CRC of mitochondria obtained from the brains of cKO and control mice. Large-scale, genome-wide association studies of the disease, however, highlighted FADS1,2 genes involved in the polyunsaturated fatty acids metabolism.…”

Genome‐wide association studies of bipolar disorder: A systematic review of recent findings and their clinical implications

“…Another interesting and novel susceptibility gene is Fatty acid desaturase 1/2/3 ( FADS1/2/3 ), which was detected by our research group (advanced COSMO) . It is also noteworthy that this study used a non‐European sample and was the largest in the East Asian population.…”

“…Therefore, it is difficult to pinpoint the ‘genuine’ susceptibility genes solely on the basis of these results. Trans‐ethnic replication analysis is reasonable for this purpose and in this aspect, it is stressed that the SNP near FADS genes were associated with BD in the updated PGC data, which indicated that the trans‐population effect exists in the FADS region as a risk for BD between European and Asian populations.…”

“…However, the number of novel susceptibility genes for BD was limited. (Note: PGC results are open and, thus, are publicly available for download at http://www.med.unc.edu/pgc/results-and-downloads/downloads; therefore, after the PGC results, the researchers used them in their discovery GWAS or replication results …”