Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Manhattan plot of genome-wide association meta-analysis of 41,917 bipolar disorder cases and 371,549 controls.The x-axis shows genomic position (chromosomes 1–22 and X), and the y-axis shows statistical significance as −log10(P value). P values are two-sided and based on an inverse variance weighted fixed effects meta-analysis. The red line shows the genome-wide significance threshold (P < 5 × 10−8). SNPs in genome-wide significant loci are colored green for loci previously associated with bipolar disorder (BD) and yellow for novel associations from this study. The genes labeled are those prioritized by integrative eQTL analyses or notable genes in novel loci (MHC, CACNB2, KCNB1).

Phenotypic variance in bipolar disorder explained by polygenic risk scores.Variance explained is presented on the liability scale, assuming a 2% population prevalence of bipolar disorder. For European ancestries, the results shown are the weighted mean R2 values across all 57 cohorts in the PGC3 meta-analysis, weighted by the effective n per cohort. The numbers of cases and controls are shown from left to right under the barplot for each study. GWAS PT, the color of the bars represents the P value threshold used to select SNPs from the discovery GWAS; GAIN-AA, Genetic Association Information Network African American cohort; AA-GPC, African American Genomic Psychiatry Cohort.

Relationships between bipolar disorder and modifiable risk factors based on genetic correlations, generalized summary statistics-based Mendelian randomization, and bivariate gaussian mixture modeling.Venn diagrams depict MiXeR results of the estimated number of influencing variants shared between bipolar disorder (BD) and each trait of interest (grey), unique to BD (blue) and unique to the trait of interest (orange). The number of influencing variants and standard error are shown in thousands. The size of the circles reflects the polygenicity of each trait, with larger circles corresponding to greater polygenicity. The estimated genetic correlation (rg) between BD and each trait of interest and standard error from LD Score regression is shown below the corresponding Venn diagram, with an accompanying scale (-1 to +1). The arrows above and below the Venn diagrams indicate the results of generalized summary statistics-based Mendelian randomization (GSMR) of BD on the trait of interest, and the trait of interest on BD, respectively. The GSMR effect size and standard error is shown inside the corresponding arrow. Solid arrows indicate a significant relationship between the exposure and the outcome, after correction for multiple comparisons (P < 1.47 × 10−3), and dashed arrows indicate a non-significant relationship.