Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Department of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
JAMA Psychiatry. 2022 Nov 1;79(11):1110-1117. doi: 10.1001/jamapsychiatry.2022.2983.
Self-reported trauma exposure has consistently been found to be a risk factor for major depressive disorder (MDD), and several studies have reported interactions with genetic liability. To date, most studies have examined gene-environment interactions with trauma exposure using genome-wide variants (single-nucleotide variations [SNVs]) or polygenic scores, both typically capturing less than 3% of phenotypic risk variance.
To reexamine genome-by-trauma interaction associations using genetic measures using all available genotyped data and thus, maximizing accounted variance.
DESIGN, SETTING, AND PARTICIPANTS: The UK Biobank study was conducted from April 2007 to May 1, 2016 (follow-up mental health questionnaire). The current study used available cross-sectional genomic and trauma exposure data from UK Biobank. Participants who completed the mental health questionnaire and had available genetic, trauma experience, depressive symptoms, and/or neuroticism information were included. Data were analyzed from April 1 to August 30, 2021.
Trauma and genome-by-trauma exposure interactions.
Measures of self-reported depression, neuroticism, and trauma exposure with whole-genome SNV data are available from the UK Biobank study. Here, a mixed-model statistical approach using genetic, trauma exposure, and genome-by-trauma exposure interaction similarity matrices was used to explore sources of variation in depression and neuroticism.
Analyses were conducted on 148 129 participants (mean [SD] age, 56 [7] years) of which 76 995 were female (52.0%). The study approach estimated the heritability (SE) of MDD to be approximately 0.160 (0.016). Subtypes of self-reported trauma exposure (catastrophic, adult, childhood, and full trauma) accounted for a significant proportion of the variance of MDD, with heritability (SE) ranging from 0.056 (0.013) to 0.176 (0.025). The proportion of MDD risk variance accounted for by significant genome-by-trauma interaction revealed estimates (SD) ranging from 0.074 (0.006) to 0.201 (0.009). Results from sex-specific analyses found genome-by-trauma interaction variance estimates approximately 5-fold greater for MDD in male participants (0.441 [0.018]) than in female participants (0.086 [0.009]).
This cross-sectional study used an approach combining all genome-wide SNV data when exploring genome-by-trauma interactions in individuals with MDD; findings suggest that such interactions were associated with depression manifestation. Genome-by-trauma interaction accounts for greater trait variance in male individuals, which points to potential differences in depression etiology between the sexes. The methodology used in this study can be extrapolated to other environmental factors to identify modifiable risk environments and at-risk groups to target with interventions.
自我报告的创伤暴露一直被认为是重度抑郁症（MDD）的风险因素，并且有几项研究报告了与遗传易感性的相互作用。迄今为止，大多数研究使用全基因组变体（单核苷酸变异[SNV]）或多基因评分来检查创伤暴露与基因-环境相互作用，这两种方法通常仅能捕捉到不到 3%的表型风险变异。
使用遗传措施重新检查使用全基因组数据的基因组与创伤暴露的相互作用关联，从而最大限度地解释方差。
设计、设置和参与者：英国生物库研究于 2007 年 4 月至 2016 年 5 月 1 日（后续心理健康问卷调查）进行。本研究使用英国生物库的现有横断面基因组和创伤暴露数据。纳入完成心理健康问卷调查且具有可用遗传、创伤经历、抑郁症状和/或神经质信息的参与者。数据分析于 2021 年 4 月 1 日至 8 月 30 日进行。
创伤和基因组与创伤暴露的相互作用。
英国生物库研究提供了自我报告的抑郁、神经质和创伤暴露的全基因组 SNV 数据。在这里，使用遗传、创伤暴露和基因组与创伤暴露相互作用相似性矩阵的混合模型统计方法，探讨了抑郁和神经质变化的来源。
在 148129 名参与者（平均[标准差]年龄为 56[7]岁）中进行了分析，其中 76995 名参与者为女性（52.0%）。该研究方法估计 MDD 的遗传度（SE）约为 0.160（0.016）。自我报告的创伤暴露（灾难性、成人、儿童和全创伤）亚型占 MDD 变异的很大一部分，遗传度（SE）范围为 0.056（0.013）至 0.176（0.025）。由显著的基因组与创伤相互作用解释的 MDD 风险变异比例显示，估计值（SD）范围为 0.074（0.006）至 0.201（0.009）。男性参与者（0.441[0.018]）中 MDD 的基因组与创伤相互作用变异估计值约为女性参与者（0.086[0.009]）的 5 倍。
这项横断面研究在探索 MDD 个体的基因组与创伤相互作用时，结合了所有全基因组 SNV 数据的方法；研究结果表明，这种相互作用与抑郁表现有关。基因组与创伤相互作用在男性个体中占更大的特质方差，这表明性别之间的抑郁病因可能存在差异。本研究中使用的方法可以推广到其他环境因素，以确定可改变的风险环境和高危人群，以便进行干预。
