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. 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.
Original language | English |
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Journal | Journal of Affective Disorders |
Volume | 359 |
Pages (from-to) | 382-391 |
Number of pages | 10 |
ISSN | 0165-0327 |
DOIs | |
Publication status | Published - 15 Aug 2024 |
MoE publication type | A1 Journal article-refereed |
Bibliographical note
Publisher Copyright:© 2024 The Authors
Fields of Science
- Childhood stress
- Dopamine beta-hydroxylase
- Dopamine receptor D2
- Major depression
- Methylenetetrahydrofolate reductase
- Tryptophan hydroxylase 1
- 3121 General medicine, internal medicine and other clinical medicine