背景:重度抑郁症(MDD)在合并症方面具有相当大的异质性,这可能会阻碍其生物学机制的解开。在之前的研究中,我们将MDD相关多发病率的终生轨迹分为七个不同的簇,每种都具有独特的遗传和环境风险因素特征。当前的目标是调查全基因组基因-环境(G×E)与儿童创伤负担的相互作用,在这些集群的背景下。
方法:我们分析了英国生物库数据库的77,519名参与者和6,266,189个单核苷酸多态性(SNP)。使用儿童创伤筛选器(CTS)评估儿童创伤负担。对于每个集群,用Plink2.0计算SNP×CTS相互作用对参与者集群成员概率的影响。我们特别关注从先前的G×E研究中选择的31个候选基因和相关SNP对儿童虐待与抑郁症的关联的影响。
结果:在SNP级别,只有高多发病率簇6显示了全基因组显著的SNPrs145772219。在基因层面,MPST和PRH2分别对低多浊度簇1和3具有全基因组意义。关于G×E相互作用的候选SNP,单个SNP结果可以被复制为特定的簇。候选基因CREB1、DBH、和MTHFR(第5组)以及TPH1(第6组)在多次测试校正中幸存。
结论:CTS是一种简短的回顾性自我报告测量。集群可能受到个体疾病遗传的影响。
结论:针对MDD相关多发病轨迹的第一个G×EGWAS成功复制了先前与抑郁相关的G×E研究的发现,并揭示了童年创伤的风险集群。
BACKGROUND: Major depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters.
METHODS: We analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants\' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment\'s association with depression.
RESULTS: At SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction.
CONCLUSIONS: CTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders.
CONCLUSIONS: The first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma.