Causal inference in psychopathology: Using Mendelian randomisation to identify environmental risk factors for psychopathology

Psychopathology represents a leading cause of disability worldwide. Effective interventions need to target risk factors that are causally related to psychopathology. In order to distinguish between causal and spurious risk factors, it is critical to account for, environmental and genetic confounding. Mendelian randomisation studies use genetic variants that are independent from environmental and genetic confounders in order to strengthen causal inference. We conducted a systematic review of fifteen studies using Mendelian randomisation to examine the causal role of putative risk factors for psychopathology related outcomes including depression, anxiety, psychological distress, schizophrenia, substance abuse/antisocial behaviour, and smoking initiation. The most commonly examined risk factors in the reviewed Mendelian randomisation studies were smoking, alcohol use and body mass index. In most cases, risk factors were strongly associated with psychopathology-related outcomes in conventional analyses. Conversely, Mendelian randomisation analyses provided very little consistent evidence that any of these associations were causal. We discuss possible reasons for these diverging results between conventional and Mendelian randomisation analyses and outline future directions for progressing research in ways that maximises the potential for identifying targets for intervention.