Chunk #20 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Pleiotropy, confounding, and causal inference
Prior work has clarified causality for many phenotypes. One of the most instructive examples of MR relates to coronary heart disease (CHD). CHD is genetically and epidemiologically correlated with elevated BMI, high levels of low-density lipoprotein (LDL) cholesterol and triglycerides, and low levels of high-density lipoprotein (HDL) cholesterol. However, notwithstanding these correlations, MR shows that HDL does not causally impact CHD risk (44; 45) (Figure 3). This explains why previous clinical trials with drugs aimed at raising HDL levels failed to decrease CHD risk. This demonstrates that MR can shape therapeutic strategies—while precisely measured biomarkers such as HDL that are correlated with disease outcomes such as CHD have some value for predictive modeling, perturbing HDL levels is an invalid strategy for reducing CHD risk. In psychiatry, MR has demonstrated the protective influence of accelerometer-based physical activity on major depression but no opposite relationship of depression influencing physical activity (46).
