Previous genome-wide association studies of depression have primarily focused on common variants, limiting our comprehensive understanding of the genetic architecture. In contrast, whole–exome sequencing can capture rare coding variants, helping to explore the phenotypic consequences of altering protein-coding genes. Here, we conducted a large-scale exome-wide association study on 296,199 participants from the UK Biobank, assessing their depressive symptom scores through the Patient Health Questionnaire-4. We identified 22 genes associated with depressive symptoms, including 6 newly discovered genes (TRIM27, UBD, SVOP, ADGRB2, IRF2BPL, and ANKRD12). Both ontology enrichment analysis and plasma proteomics association analysis consistently revealed that the identified genes were associated with immune responses. Furthermore, we identified associations between these genes and brain regions related to depression, such as anterior cingulate cortex and orbitofrontal cortex. Additionally, phenome-wide association analysis demonstrated that TRIM27 and UBD were associated with neuropsychiatric, cognitive, biochemistry, and inflammatory traits. Our findings offer new insights into the potential mechanisms and genetic architecture of depressive symptoms.

以前抑郁症的全基因组关联研究主要集中在常见变异上，限制了我们对遗传结构的全面理解。相比之下，全外显子组测序可以捕获罕见的编码变异，有助于探索改变蛋白质编码基因的表型后果。在这里，我们对来自英国生物样本库的 296,199 名参与者进行了一项大规模的外显子组范围关联研究，通过患者健康问卷 4 评估他们的抑郁症状评分。我们确定了 22 个与抑郁症状相关的基因，包括 6 个新发现的基因 （TRIM27 、 UBD 、 SVOP 、 ADGRB2 、 IRF2BPL 和 ANKRD12）。本体富集分析和血浆蛋白质组学关联分析一致表明，鉴定的基因与免疫反应相关。此外，我们确定了这些基因与抑郁症相关的大脑区域之间的关联，例如前扣带皮层和眶额叶皮层。此外，表型组范围关联分析表明，TRIM27 和 UBD 与神经精神病、认知、生物化学和炎症特征相关。我们的研究结果为抑郁症状的潜在机制和遗传结构提供了新的见解。