Pasman Joëlle A, Bergstedt Jacob, Harder Arvid, Gong Tong, Xiong Ying, Hägg Sara, Fang Fang, Treur Jorien L, Choi Karmel W, Sullivan Patrick F, Lu Yi
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Nobels Väg 12, Stockholm, Sweden.
Amsterdam UMC location University of Amsterdam, Department of Psychiatry, Genetic Epidemiology, Meibergdreef 9, Amsterdam, The Netherlands.
medRxiv. 2024 May 21:2024.05.21.24307678. doi: 10.1101/2024.05.21.24307678.
Major depressive disorder (MDD) is a prevalent and debilitating disorder that has been associated with a range of risk factors and outcomes. Causal pathways between MDD and other traits can be studied using genetic variants as instrumental variables.
A literature review was conducted to identify 201 MDD-associated traits. For 115 traits, there were well-powered genome-wide association study (GWAS) results available that could be used to assess the genetic correlation with MDD. Of these, there were 89 meeting criteria for investigating causal associations in both directions using two-sample Mendelian randomization (TSMR). Of the traits that were not captured by GWAS, 43 could be included as outcomes of MDD using one-sample MR (OSMR). A range of methods and sensitivity tests was applied to gauge robustness of results, together with statistical power analyses to aid interpretation.
Moderate to strong genetic overlap was found between MDD and most traits. Support for causal effects of MDD liability were found for circadian, cognitive, diet, medical disease, endocrine, functional, inflammatory, metabolic, mortality, physical activity, reproduction, risk behavior, social, socioeconomic, and suicide outcomes. Most associations were bidirectional, although there was less evidence for diet, disease, and endocrine traits causing MDD risk. Results were robust across sensitivity analyses.
This study provides a systematic overview of traits putatively causally related to MDD, confirming previous findings as well as identifying new associations. Our results highlight the importance of MDD as a risk factor cross-cutting across medical, functional, and psychosocial domains and emphasize the need for concerted efforts at reducing this highly prevalent disorder.
重度抑郁症（MDD）是一种常见且使人衰弱的疾病，与一系列风险因素和后果相关。可以使用基因变异作为工具变量来研究MDD与其他特征之间的因果途径。
进行了一项文献综述，以确定201个与MDD相关的特征。对于115个特征，有功效强大的全基因组关联研究（GWAS）结果可用于评估与MDD的遗传相关性。其中，有89个符合使用双样本孟德尔随机化（TSMR）双向研究因果关联的标准。在未被GWAS捕获的特征中，43个可以作为单样本MR（OSMR）中MDD的结果纳入。应用了一系列方法和敏感性测试来评估结果的稳健性，并进行统计功效分析以辅助解释。
在MDD与大多数特征之间发现了中度至高度的遗传重叠。在昼夜节律、认知、饮食、医学疾病、内分泌、功能、炎症、代谢、死亡率、身体活动、生殖、风险行为、社会、社会经济和自杀结果方面，发现了支持MDD易感性因果效应的证据。大多数关联是双向的，尽管饮食、疾病和内分泌特征导致MDD风险的证据较少。敏感性分析结果具有稳健性。
本研究系统概述了与MDD可能存在因果关系的特征，证实了先前的发现并确定了新的关联。我们的结果强调了MDD作为贯穿医学、功能和心理社会领域的风险因素的重要性，并强调需要共同努力减少这种高度流行的疾病。
