The use of Mendelian randomization to explore the causal consequences of childhood maltreatment: consideration of assumptions and challenges

Mendelian randomization (MR) uses genetic variants as instrumental variables to enhance causal inference. Studies have identified genetic variants related to childhood maltreatment, but interpreting the effects of these variants or assessing the plausibility of MR assumptions is complex. We aim to investigate the feasibility of applying MR to complex social traits using the association between childhood maltreatment and mental health and behavioral outcomes as an example. We explore four potential key concerns: confounding by population phenomena, horizontal pleiotropy, reverse causality, and selection. For each concern, we demonstrate scenarios where MR studies of childhood maltreatment may be biased using DAGs and critical appraisal of previous MR analyses. For confounding by population phenomena, we further perform within-family genetic analyses in 42,101 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) to address bias due to family-level processes since childhood maltreatment often occurs within households. Our results showed same-trait shrinkage (11% attenuation of the association between children’s polygenic risk scores of childhood maltreatment (PRS _CM ) and mothers’ report of children’s physical abuse) but not cross-trait shrinkage (children’s PRS _CM and children’s mental health and behavioral outcomes) after adjusting for parental PRS _CM . The lack of cross-trait shrinkage suggests that genetic variants related to childhood maltreatment may be capturing other child-level phenotypes, after adjusting for family-level processes. Mothers’ PRS _CM were also associated with mothers’ own maltreatment experiences in childhood and adulthood with similar magnitudes, suggesting these genetic effects are not specific to childhood maltreatment. Due to the complexity involved in the causal chain of childhood maltreatment and it being reported, the interpretation of MR studies for childhood maltreatment is challenging. Other causal approaches should be considered for observational studies of complex social traits.