Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

目前大多数为精准医疗建立抑郁症患者亚组的方法都旨在依赖需要高度专业化评估的生物标志物。我们目前的目标是根据三个易于测量的常见独立风险因素对英国生物银行队列的参与者进行分层，并研究每组的抑郁症基因组学，以发现共同和单独的生物学病因。对男性（ n  = 149,879）和女性（n = 174,572）分别进行两步聚类分析 ，以神经质（体验负面情绪的倾向）、体脂百分比和受教育年限作为输入变量。在每个产生的簇中进行全基因组关联分析，以抑郁发作或复发性抑郁症的终生发生率作为结果。应用基于变体、基于基因、基于基因集和组织特异性的基因表达测试。在抑郁症基因组学中发现了具有高度遗传相关性的表型不同的簇。两簇解决方案是每种性别的最佳模型，但存在一些差异，包括男性中神经质的作用不太重要。在女性中，在低神经质、低体脂百分比和高教育水平的保护模式下，抑郁症与嗅觉功能相关通路有关。虽然女性也存在抑郁症，但其风险模式包括高度神经质、高体脂百分比和受教育年限较短，抑郁症与补体系统基因有关。一方面，我们的结果表明，嗅觉通路的改变，可以与众所周知的嗅球切除术的啮齿动物抑郁模型平行，可能是对其他抑郁危险因素较少的女性进行精确精神病学的新目标。另一方面，我们在多风险女性中的结果可能提供免疫代谢抑制的特殊情况。