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

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 C6orf89 and 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.