Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10^-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Figure 1:. Case-control enrichment of ultra-rare variants, split by case status and consequence category.

a) Enrichment in cases over controls (n=14,422) in case subsets (BD cases: n=13,933, BD1 cases: n=8,238, BD2 cases: n=3,446), according to the legend. The midpoint displays the logistic regression estimate. Bars show the 95% confidence intervals on the logistic regression estimate of the enrichment of the class of variation labelled on the x-axis. b,c) Case-control enrichment and excess case rare variant burden in increasingly a priori damaging variant subsets using logistic and linear regression, respectively. Consequence categories are stratified by rarity: moving from left to right the putatively damaging nature of the variants reduces from dark red to pink according to the legend, and the rarity reduces from a variant with MAC≤5 in a pLI≥0.9 gene and not in the non-neurological portion of gnomAD (Not in gnomAD pLI≥0.9), to a variant with MAC≤5 (All) according to the x-axis labelling. In (b), midpoints and bars display the logistic regression estimates, and associated 95% confidence intervals of the enrichment of the class of variation labelled on the x-axis. In (c), midpoints and bars show the linear regression estimates on excess variants in cases, and associated 95% confidence intervals for the class of variation labelled on the x-axis. Regressions are run as described in Methods: exome-wide burden, and include sex, 10 principal components and total coding burden with the same rarity as covariates. Nominally significant enrichments or excess variants in cases are labelled with the unadjusted associated two-sided P-value computed using a Wald test.

Figure 2:. Biological insights from bipolar case-control whole-exome sequencing data.

a) Enrichment of ultra-rare PTVs in BD cases over controls in tissue-specific expression gene-sets. We run logistic regressions of case status on ultra-rare PTV burden in tissue-specific expression gene-sets. Logistic regressions were performed as described in the Supplementary Note. Two-sided P-values were obtained via Wald tests. Gene-sets are defined in Finucane et al. in detail. Bars are ordered by P-value, first for brain tissue and then for other tissues. No nominally significant association was enriched in controls over BD cases. b) Enrichment of ultra-rare variants in targeted 68 gene-sets taken from the literature^,. We run logistic regressions of case status on ultra-rare variant burden in classes of variation labelled in the legend, and display the expected against observed two-sided unadjusted −log(P-values). Logistic regressions were performed as described in Methods. Two-sided P-values were obtained via Wald tests. Top PTV and damaging missense gene-sets are labelled, and annotated with the number of genes in each gene-set. The 95% confidence interval under the null, is shown in grey. Classes of variants tested in each gene-set are colored according to the legend. Gene-sets surpassing Bonferroni test correction are labelled with an asterisk. hNSC, human neuronal stem cells.

Figure 3:. Results of the analysis of ultra-rare PTVs in 13,933 cases and 14,422 controls. Gene-based Manhattan and QQ plot for BD (comprising BD1, BD2 and BDNOS).

−log10 P-values obtained via two-sided Fisher’s exact tests are plotted against genetic position for each of the analyzed genes. In the QQ plots, observed −log10 P-values are plotted against permutation P-values according to the procedure described in the Methods. Points are colored according to the discrete scale displayed in the legend. In the Manhattan plot and QQ plot, the gene symbols of the top 20 and top ten genes by P-value are labelled, respectively. Points in the Manhattan plot are sized according to P-value as displayed in the legend.