BACKGROUND Major depression (MD) is determined by a multitude of factors including genetic risk variants that regulate gene expression. We examined the genetic component of gene expression in MD by performing a transcriptome-wide association study (TWAS), inferring gene expression-trait relationships from genetic, transcriptomic, and phenotypic information. METHODS Genes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (n = 135,458 cases, n = 344,901 controls) and gene expression levels from 21 tissue datasets (brain; blood; thyroid, adrenal, and pituitary glands). Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with TWAS-based pathway investigations. RESULTS Transcriptome-wide significant differences between cases and controls were found at 94 genes, approximately half of which were novel. Of the 94 significant genes, 6 represented strong, colocalized, and potentially causal associations with depression. Such high-confidence associations include NEGR1, CTC-467M3.3, TMEM106B, LRFN5, ESR2, and PROX2. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for, among others, neuronal and synaptic processes. CONCLUSIONS This study sheds further light on the genetic component of gene expression in depression by characterizing the identified associations, unraveling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.

中文翻译：

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描述重度抑郁症基因表达的遗传成分

背景 重性抑郁症 (MD) 由多种因素决定，包括调节基因表达的遗传风险变异。我们通过进行全转录组关联研究 (TWAS)，从遗传、转录组和表型信息推断基因表达-性状关系，检查了 MD 中基因表达的遗传成分。方法 基于最大的 MD 全基因组关联分析（n = 135,458 例，n = 344,901 对照）和 21 个组织数据集（大脑；血液；甲状腺、肾上腺和垂体）。进行了后续分析以广泛表征已识别的关联：共定位、条件、和精细映射分析以及基于 TWAS 的通路调查。结果 在 94 个基因中发现了病例和对照之间的转录组范围内的显着差异，其中大约一半是新的。在 94 个重要基因中，6 个代表与抑郁症的强烈、共定位和潜在的因果关联。这种高可信度的关联包括 NEGR1、CTC-467M3.3、TMEM106B、LRFN5、ESR2 和 PROX2。最后，基于 TWAS 的富集分析强调了神经元和突触过程等基因组的失调。结论 本研究通过表征已识别的关联、解开新的风险基因并确定哪些关联与因果模型一致，进一步阐明了抑郁症基因表达的遗传成分。