Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well-characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets. Furthermore, we showed targeted downstream GPCR dysregulation for some of the variants that may contribute to disease pathology. Particularly interesting was the finding of a rare and functionally relevant nonsense mutation in the corticotropin-releasing hormone receptor 2 (CRHR2) gene that tracked with affected status in one family. By focusing on rare variants in informative families, we identified key biochemical pathways likely implicated in this complex disorder.

中文翻译：

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双相情感障碍的罕见药敏性变异提示G蛋白偶联受体的作用。

躁郁症（BD）是一种普遍的情绪障碍，倾向于聚集在家庭中。尽管对遗传力的估计很高，但在数十年的遗传研究中几乎没有发现遗传易感性因素。先前研究检测致病基因的缺点的一种可能解释是，BD是由许多基因中高度渗透的稀有变异体引起的。我们通过对来自40个特征明确的多重家族的受影响个体的外显子进行测序，探索了这一假设。我们鉴定了在许多有趣的基因中处于受影响状态的稀有变异体，并发现了G蛋白偶联受体（GPCR）家族基因中的有害变异体富集，这些都是重要的药物靶标。此外，对于某些可能导致疾病病理的变异，我们显示了针对性的下游GPCR失调。特别令人感兴趣的是在促肾上腺皮质激素释放激素受体2（CRHR2）基因中发现了一种罕见且功能相关的无意义突变，该突变可追踪一个家庭的患病状况。通过关注信息丰富的家族中的稀有变异，我们确定了可能与这种复杂疾病有关的关键生化途径。