Abstract
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.
Highlights
Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes
When all germline DNMs (gDNMs), including those observed in the general population in the Genome Aggregation Database or the Tohoku Medical Megabank Organization (ToMMo28), were subjected to the analysis, there was no significant difference in the rates of any functional types of gDNMs between Bipolar disorder (BD) and controls (Fig. 1a)
On the other hand, when we filtered out all the variants observed in gnomAD or ToMMo (“Methods”), we observed a trend toward the enrichment of LoF and damaging missense/inframe indel gDNMs in BD (Fig. 1b, uncorrected P = 0.0931 for LoF and 0.0502 for damaging missense/inframe indel), whereas the rates of non-damaging missense and synonymous gDNMs were similar between BD and controls
Summary
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. An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are 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. Our analysis of the genes hit by deleterious gDNMs or pzDNMs in BD provides insights into its neurobiology, including biological pathways related to BD and neuronal cell types possibly playing a critical role in the disease etiology
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