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 6882 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 postsynaptic density (PSD) (all Bonferroni corrected p < 0.05). Pathway analyses showed enrichment in several pathways, including “Phosphoinositides (PI) and their downstream targets” (Bonferroni p = 4.2 × 10⁻⁶), a pathway prominently featured in lithium’s hypothesized mechanism of action. In addition, while we found overall evidence for transmission of common variant polygenic risk of BD in our full sample (pTDT p = 2.21 × 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.

双相情感障碍 (BD) 是一种常见的高度遗传性疾病，影响着世界 1-2% 的人口。迄今为止，大多数双相情感障碍的遗传学研究都集中在常见的基因变异上，虽然已经确定了强有力的相关位点，但很大一部分遗传力仍然缺失，并且可能部分归因于罕见变异。在这项研究中，我们在 BD 中应用从头范例来识别尚未经过自然选择并可能代表高致病性变异的新出现的变异。我们对 97 名德系犹太人后裔进行了全基因组测序，选择了没有 BD 家族史且发病年龄较早的“单纯”家庭。我们总共发现了 6882 个从头变异（每个三组平均有 70.9 ± 12.9 个 SD 变异），其中包括蛋白质编码基因内的 107 个变异。我们将外显子变异与之前发表的 79 个 BD 三重奏的结果相结合，识别出 BD 中的 20 个功能丧失 (LoF) 和 77 个错义破坏性从头变异。这些变异显示出受限基因和位于突触后密度 (PSD) 的基因显着富集（所有 Bonferroni 校正p < 0.05）。途径分析显示多种途径的富集，包括“磷酸肌醇 (PI) 及其下游靶标”(Bonferroni p = 4.2 × 10 ^-6 )，这是锂假设作用机制中的一个突出特征的途径。此外，虽然我们在完整样本中发现了 BD 常见变异多基因风险传播的总体证据 (pTDT p = 2.21 × 10 ^-4 )，但具有 LoF 变异的特定三重奏没有显示多基因传播的证据。 总之，我们的研究结果支持从头范式作为 BD 遗传结构的贡献者，并提供了证据，证明受限基因以及 PSD 和 PI 途径内的基因存在与 BD 相关的罕见变异。