Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P=0.0410) and deleterious mutations in presynaptic active zone genes (FDR=0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P=0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder. The significance of rare and de novo variants in bipolar disorder is not well understood. Here, the authors have analyzed whole exome/genome data from trios to identify deleterious de novo variants associated with bipolar disorder.

Automated summary

This study analyzed rare genetic mutations in trios with bipolar disorder, finding contributions of both germline and postzygotic mutations to the risk of the disorder. The analysis supports the hypothesis that postzygotic mutations of developmental disorder genes may play a role in bipolar disorder.