Chunk #22 — Limitations and misunderstandings of clinical, translational, and research applications of PRS — Eurocentric GWAS biases limit the generalizability of genetic risk prediction
The vast majority of GWAS have been conducted in individuals of European descent (50–55), limiting diverse applications of PRS, and introducing unpredictable directional biases across populations (56). Importantly, trans-ethnic PRS often explain many-fold less of the heritable variation than in the study population (24; 55–57), as has been demonstrated for psychosis in African Americans when predicted from European GWAS (32; 58). Previous studies have shown a roughly 2- to 5-fold reduction in heritable variation explained in East Asians and African Americans relative to Europeans, respectively (55; 59; 60). Spurious GWAS associations are also possible within Europe if population stratification is not properly accounted for (61), creating downstream interpretation challenges when PRS are computed from confounded GWAS. Further, differ environmental factors can non-causally associate with genetic divergence, such as access to clean drinking water during development. While many psychiatric disorders are highly heritable, some environmental factors can dwarf individual genetic effect sizes and create issues of comparability across diverse populations. Critically needed statistical methods are being developed to improve the generalizability of genetic risk scores across diverse populations, including our own
