Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

重度抑郁症（MDD）是一种世界范围内常见的精神疾病，是由环境和遗传因素之间复杂的相互作用引发的。尽管有多项针对 MDD 常见变异的研究，但对罕见变异的研究相对有限。此外，很少有研究使用全外显子组测序（WES）来研究遗传对 MDD 神经结构改变的影响。我们对 367 名 MDD 患者和 161 名健康对照 (HC) 进行了 WES，以检测韩国人群的种系和拷贝数变异。我们分析了基于基因的罕见变异，以研究基因与个体之间的关联，随后进行神经影像-遗传分析，利用弥散张量成像数据探索 234 名 MDD 患者和 135 名 HC 患者遗传影响背后的神经机制。我们鉴定了 40 个 MDD 相关基因，并观察了 95 个拷贝数变异的重复区域。我们还发现了一种新基因FRMPD3，它携带影响 MDD 的罕见变异。此外，MUC6基因中的单核苷酸多态性rs771995197与广泛分布的白质束的完整性显着相关。此外，我们在与 MDD 易感性相关的基因中鉴定出了 918 个罕见的外显子错义变异。我们假设FRMPD3的罕见变体可能对 MDD 有显着影响，并具有轻微的渗透效应。