Biological pathways underlying the relationship between childhood maltreatment and Multimorbidity: A two-step, multivariable Mendelian randomisation study

2025/02/01 by Vilte Baltramonaityte, Ville Karhunen, Janine F. Felix +5 · 1 voice
Medicine · Health Professions · #Birth, Development, and Health #Adolescent and Pediatric Healthcare #Child and Adolescent Health

paper · doi:10.1016/j.bbi.2025.01.024

openalex publication_date 2025/02/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31

Abstract

• Metabolic pathways mediate the effect of childhood maltreatment on multimorbidity. • No evidence of mediation via inflammatory proteins or cortisol. • Metabolic alterations in maltreated individuals may increase multimorbidity risk. Childhood maltreatment has been associated with multimorbidity of depression, coronary artery disease and type 2 diabetes. However, the biological mechanisms underlying this association remain unclear. We employed two-step and multivariable Mendelian randomisation (MR) to understand the role of three potential biological mediating mechanisms – inflammation (92 proteins), metabolic processes (54 markers), and cortisol – in the link between childhood maltreatment liability and multimorbidity. Using summary statistics from large-scale genome-wide association studies of European ancestry for childhood maltreatment ( N = 185,414) and multimorbidity ( N effective = 156,717), we tested for the presence of an indirect effect via each mediator individually. We found a potential role of metabolic pathways. Up to 11 % of the effect of childhood maltreatment on multimorbidity was mediated by triglycerides (indirect effect [95 %CI]: 0.018 [0.009–0.027]), 8 % by glycated haemoglobin (indirect effect: 0.013 [0.003–0.023]), and up to 7 % by high-density lipoprotein cholesterol (indirect effect: 0.011 [0.005–0.017]). We did not find evidence for mediation via any inflammatory protein or cortisol. Our findings shed light on the biological mechanisms linking childhood maltreatment liability to multimorbidity, highlighting the role of metabolic pathways. Future studies may explore underlying pathways via non-biological mediators (e.g., lifestyle factors) or via multiple mediators simultaneously.

Citations

• Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors
• Mendelian randomisation for mediation analysis: current methods and challenges for implementation
• Computationally efficient whole-genome regression for quantitative and binary traits
• Testing and correcting for weak and pleiotropic instruments in two‐sample multivariable Mendelian randomization
• Mendelian randomization

Discussions

• New collaboration published in @brainbehavimm.bsky.social Analyses leveraging #genetic data highlighted the potential role of #metabolic alterations (e.g., dyslipidemia, dysglycemia) as mechanisms con [bsky, 2 points, 0 comments]

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