Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder

Abstract

Bipolar disorder is a highly heritable psychiatric disorder; genome-wide association studies of bipolar disorder have yielded over 60 risk loci harboring common variants. To harness the information contained in rare loss-of-function (LOF) variants, holding promise for informing on the underlying biology, we performed a variant burden analysis for bipolar disorder using gene-based aggregation of LOF variants in whole-genome sequencing data from Iceland (4,197 cases, more than 200,000 controls) and the UK Biobank (1,881 cases, 426,622 controls). We found that HECTD2 was associated with bipolar disorder and confirmed it using the Bipolar Exome dataset. Meta-analysis with Bipolar Exome also revealed that LOF variants in AKAP11 were associated with bipolar disorder. Both associations with bipolar disorder are new, but AKAP11 has previously been associated with psychosis and schizophrenia. The products of AKAP11 and HECTD2 interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer available to treat bipolar disorder.

Fig. 1. Gene-based Manhattan plot for the ICE-UKB meta-analysis.

The plot shows −log₁₀ P values against the chromosomal position of each of the genes studied. The top 20 findings are indicated by the green dots; the corresponding gene name is represented by the most proximal gene symbol. The results for the top 20 genes, for the meta-analysis and for each study (ICE and UKB), are provided in Supplementary Table 1. Logistic regression was used to test for association in ICE and UKB, obtaining the P values from a likelihood ratio test corrected for cryptic relatedness and stratification. The meta-analysis used the fixed-effect inverse variance-weighted method. The P values presented were not corrected for multiple testing, but the red line represents a Bonferroni threshold of P ≤ 3.6 × 10⁻⁶.

Fig. 2. Gene-based Manhattan plot for the ICE-UKB-BipEx meta-analysis.

The plot shows −log₁₀ two-sided P values against the chromosomal position of each of the genes studied. The top 20 findings are indicated by the green dots; the corresponding gene name is represented by the most proximal gene symbol. Logistic regression was used to test for association in ICE and UKB; P values were obtained from a likelihood ratio test adjusted for cryptic relatedness and stratification. The results, including ORs, for the top 20 genes for the meta-analysis and for each study (ICE, UKB and BipEx) are provided in Supplementary Table 2. To obtain the overall P values, the results of the ICE-UKB fixed-effect meta-analysis (Fig. 1) were combined with the BipEx results on the z-score. The P values presented were not corrected for multiple testing, but the red line represents a Bonferroni threshold of P ≤ 3.6 × 10⁻⁶.