Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters

Abstract

Abstract 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 76,856 participants and 3,875,386 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, LDLRAD4 was genome-wide significant for the low-multimorbidity Cluster 1 and C6orf89and TAAR2 for the high-multimorbidity Cluster 7. Regarding candidate SNPs for G×E interactions, individual SNP results could be replicated for specific clusters. The candidate genes DRD2 (Cluster 1), and DBH and MTHFR (both Cluster 5), and TPH1(Cluster 6) survived multiple testing correction. Limitations: 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.