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

Sarah Bonk, Nora Eszlari, Kevin Kirchner, Andras Gezsi, Linda Garvert, Mikko Kuokkanen, Isaac Cano, Hans J. Grabe, Peter Antal, Gabriella Juhasz, Sandra Van der Auwera

Research output: Contribution to journalArticleScientificpeer-review

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 languageEnglish
JournalJournal of Affective Disorders
Volume359
Pages (from-to)382-391
Number of pages10
ISSN0165-0327
DOIs
Publication statusPublished - 15 Aug 2024
MoE publication typeA1 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

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