Bipolar Disorder (BD) is a common, highly heritable disorder that affects 1-2% of the world’s population. To date, most genetic studies of BD have focused on common gene variation, and, while robustly associated loci have been identified, a substantial proportion of the heritability remains missing and could be partially attributable to rare variation. In this study, we apply a de novo paradigm in BD to identify newly arisen variants that have yet to undergo natural selection and may represent highly pathogenic variants. We performed whole genome sequencing of 97 trios of Ashkenazi Jewish descent, selecting “simplex” families with no family history of BD and an early age of onset. We found a total of 6,882 de novo variants (an average of 70.9 ± 12.9 S.D. variants per trio), including 107 variants within protein coding genes. We combined our exonic variations with the results of 79 previously published BD trios, identifying 20 Loss of Function (LoF) and 77 missense damaging de novo variants in BD. These variants showed significant enrichment for constrained genes and for genes located to the post-synaptic density (PSD) (all Bonferonni corrected p < 0.05). Pathway analyses showed enrichment in several pathways, including “Phosphoinositides (PI) and their downstream targets” (Bonferroni p = 4.2 x 10 −6 ), a pathway prominently featured in lithium’s hypothesized mechanism of action. Additionally, while we found overall evidence for transmission of common variant polygenic risk of BD in our full sample (pTDT p =2.21x 10 −4 ), specific trios with LoF variants showed no evidence of polygenic transmission. In sum, our findings support the de novo paradigm as a contributor to the genetic architecture of BD and provide evidence that constrained genes, as well as genes within the PSD and PI pathway harbor rare variation associated with BD.

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