Replication Data for: GWAS Meta-Analysis Reveals Shared Genes and Biological Pathways between Major Depressive Disorder and Insomnia

Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide. Among the symptoms of MDD, sleep disturbance such as insomnia is prominent, and the first reason patients may seek professional help. However, the underlying pathophysiology of this comorbidity is still elusive. Recently, genome-wide association studies (GWAS) have begun to unveil the genetic background of several psychiatric disorders, including MDD and insomnia. Identifying the shared genomic risk loci between comorbid psychiatric disorders could be a valuable strategy to understanding their comorbidity. This study seeks to identify the shared genes and biological pathways between MDD and insomnia based on their shared genetic variants. First, we performed a meta-analysis based on the GWAS summary statistics of MDD and insomnia obtained from Psychiatric Genomics Consortium and UK Biobank, respectively. Next, we associated shared genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, a total of 719 shared genes were identified. Over half (51%) of them are protein-coding genes. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification, sensory perception, and immunologic signatures. We also identified druggable targets using a network approach. Together, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid MDD and insomnia symptoms.

重度抑郁症（Major depressive disorder, MDD）是全球范围内患病率最高、致残性最强的精神障碍之一。在重度抑郁症的诸多症状中，以失眠为代表的睡眠紊乱表现显著，亦是患者寻求专业诊疗的首要动因。然而，这种共病现象的潜在病理生理学机制仍未明确。近年来，全基因组关联研究（Genome-Wide Association Studies, GWAS）已开始揭示包括重度抑郁症与失眠在内的多种精神障碍的遗传背景。识别共病精神障碍间共有的基因组风险位点，或是解析其共病机制的有效途径。本研究旨在基于重度抑郁症与失眠共有的遗传变异，挖掘二者共有的基因及生物学通路。首先，我们分别基于取自精神病学基因组学联盟（Psychiatric Genomics Consortium）与英国生物银行（UK Biobank）的重度抑郁症及失眠的全基因组关联研究汇总统计数据，开展了荟萃分析。随后，我们采用两种基因定位策略，将共有的遗传变异关联至基因：(a) 基于基因组邻近性的位置定位，以及(b) 基于多组织基因表达连锁关系的表达数量性状位点（expression quantitative trait loci, eQTL）定位。最终共鉴定出719个共有基因，其中超过半数（51%）为蛋白质编码基因。功能富集分析结果显示，富集程度最高的生物学通路与表观遗传修饰、感官感知及免疫特征相关。我们还通过网络分析方法鉴定出了可药物靶向的靶点。综上，本研究结果可为解析共病的重度抑郁症与失眠症状的遗传易感性及潜在生物学通路提供新的见解。