exposure or intermediate phenotype, while the latter refers to a direct and independent genetic influence on both the exposure and the outcome [33]. Mediated pleiotropy is a single process leading to a cascade of downstream events, ultimately leading to a distal outcome. In this way, genetic variation at the FTO locus influences BMI and, in turn, blood pressure, hypertension, coronary heart disease, and so on [33]. While statistical adjustment (e.g., for BMI) can help dissect these pathways, this can be problematic where residual associations may exist due to measurement error, such as in the case of CHRNA5-A3-B4, smoking, and lung cancer risk [13]. Biological pleiotropy is more problematic and renders causal inference difficult.
