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

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.