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This review outlines four major PRS-informed design strategies: tail sampling based on PRS extremes; discordance sampling based on mismatch between phenotype and PRS-implied risk; conditional and stratified genome-wide association analyses using PRS to adjust for \/ partition background risk; and residual phenotype analysis of the component of phenotype remaining after the PRS-associated component has been removed. It thus provides a practical framework for sample enrichment, subgroup definition, and calibrated epidemiologic comparison. These designs may be especially informative when integrated with sequencing, multi-omics, longitudinal cohorts, and translationally oriented intervention studies. Their application requires careful attention to data leakage, ancestry-related bias, collider structures, and the limits of interpretation.<\/jats:p>","DOI":"10.1007\/s00439-026-02873-y","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T08:31:05Z","timestamp":1789806665000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polygenic risk scores in human genetics for study design discovery and translation"],"prefix":"10.1007","volume":"145","author":[{"given":"Hui-Qi","family":"Qu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"2873_CR1","doi-asserted-by":"publisher","first-page":"9457","DOI":"10.1038\/s41598-021-89020-x","volume":"11","author":"ET Akimova","year":"2021","unstructured":"Akimova ET, Breen R, Brazel DM, Mills MC (2021) Gene-environment dependencies lead to collider bias in models with polygenic scores. 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