{Reference Type}: Journal Article {Title}: Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters. {Author}: Bonk S;Eszlari N;Kirchner K;Gezsi A;Garvert L;Kuokkanen M;Cano I;Grabe HJ;Antal P;Juhasz G;Van der Auwera S; {Journal}: J Affect Disord {Volume}: 359 {Issue}: 0 {Year}: 2024 Aug 15 {Factor}: 6.533 {DOI}: 10.1016/j.jad.2024.05.126 {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 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.