Chunk #18 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Pleiotropy, confounding, and causal inference
While PRS are useful for studying the correlation between pairs of genotype-phenotype associations, they cannot be taken as evidence of causality, in part because PRS are a weak epidemiological instrument. A major reason is that the large number of SNPs typically used in their calculation usually have highly pleiotropic influences, in which they influence two or more different biological processes (e.g., calcium channel function in the brain and heart), which may be indirectly associated with the outcome of interest. Pleiotropy is a widespread phenomenon (38; 39) that PRS are especially sensitive to given their construction from many SNPs.
