Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3150A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

躁郁症（BD）是一种严重的精神疾病，其特征在于抑郁症和躁狂发作的复发。它的遗传力很高，并且已经进行了许多连锁和关联研究。尽管已经报道了各种连锁区域和候选基因，但是很少有显示出足够的可重复性，并且都没有基于连锁分析的结果鉴定出致病基因。为了找到预期罕见且具有强大遗传效应的功能变异，我们从一个由21名成员组成的日本家庭中招募了10名健康个体，2名身份不明的个体和6名患有BD或复发性重度抑郁症（MDD）的患者。我们使用100K单核苷酸多态性（SNP）阵列和微卫星标记进行了全基因组连锁分析，以缩小该家族中的连锁区域。随后，我们对两名BD患者进行了全外显子测序，以鉴定狭窄连锁区域的遗传突变。然后，我们对从外显子组测序结果中获得的DNA变体进行了共分离分析。最后，我们在第31外显子中鉴定出罕见的杂合突变。DOCK5（c.3150A> G，p.E1057G）。融合功能基因组学分析表明，DOCK5被列为情绪状态和自杀倾向的生物标记之一。尽管DOCK5仍然是功能未知的基因，但我们的发现突出了BD与DOCK 5之间存在病理关系的可能性。