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

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.