{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T04:56:55Z","timestamp":1772686615931,"version":"3.50.1"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S037055\/1"],"award-info":[{"award-number":["MR\/S037055\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Population differences in risk of disease are common, but the potential genetic basis for these differences is not well understood. A standard approach is to compare genetic risk across populations by testing for mean differences in polygenic scores, but existing studies that use this approach do not account for statistical noise in effect estimates (i.e., the GWAS betas) that arise due to the finite sample size of GWAS training data. Here, we show using Bayesian polygenic score methods that the level of uncertainty in estimates of genetic risk differences across populations is highly dependent on the GWAS training sample size, the polygenicity (number of causal variants), and genetic distance <jats:italic>(F<\/jats:italic><jats:sub><jats:italic>ST<\/jats:italic><\/jats:sub><jats:italic>)<\/jats:italic> between the populations considered. We derive a Wald test for formally assessing the difference in genetic risk across populations, which we show to have calibrated type 1 error rates under a simplified assumption that all SNPs are independent, which we achieve in practise using linkage disequilibrium (LD) pruning. We further provide closed-form expressions for assessing the uncertainty in estimates of relative genetic risk across populations under the special case of an infinitesimal genetic architecture. We suggest that for many complex traits and diseases, particularly those with more polygenic architectures, current GWAS sample sizes are insufficient to detect moderate differences in genetic risk across populations, though more substantial differences in relative genetic risk (relative risk &gt; 1.5) can be detected. We show that conventional approaches that do not account for sampling error from the training sample, such as using a simple <jats:italic>t<\/jats:italic>-test, have very high type 1 error rates. When applying our approach to prostate cancer, we demonstrate a higher genetic risk in African Ancestry men, with lower risk in men of European followed by East Asian ancestry.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011212","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T17:52:10Z","timestamp":1713376330000},"page":"e1011212","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bayesian approach to assessing population differences in genetic risk of disease with application to prostate cancer"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-582X","authenticated-orcid":true,"given":"Iain R.","family":"Timmins","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"The PRACTICAL Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Dudbridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"issue":"9","key":"pgen.1011212.ref001","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/ng.2368","article-title":"Evidence of widespread selection on standing variation in Europe at height-associated SNPs","volume":"44","author":"MC Turchin","year":"2012","journal-title":"Nat Genet"},{"issue":"8","key":"pgen.1011212.ref002","doi-asserted-by":"crossref","first-page":"e1004412","DOI":"10.1371\/journal.pgen.1004412","article-title":"A population genetic signal of polygenic adaptation","volume":"10","author":"JJ Berg","year":"2014","journal-title":"PLoS Genet"},{"issue":"11","key":"pgen.1011212.ref003","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/ng.3401","article-title":"Population genetic differentiation of height and body mass index across Europe","volume":"47","author":"MR Robinson","year":"2015","journal-title":"Nat Genet"},{"issue":"1","key":"pgen.1011212.ref004","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1186\/s12864-017-4262-9","article-title":"Population differentiation in allele frequencies of obesity-associated SNPs","volume":"18","author":"L Mao","year":"2017","journal-title":"BMC Genomics"},{"issue":"1","key":"pgen.1011212.ref005","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1038\/s41467-018-04191-y","article-title":"Global genetic differentiation of complex traits shaped by natural selection in humans","volume":"9","author":"J Guo","year":"2018","journal-title":"Nat Commun"},{"issue":"4","key":"pgen.1011212.ref006","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.ajhg.2017.03.004","article-title":"Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations","volume":"100","author":"AR Martin","year":"2017","journal-title":"Am J Hum Genet"},{"issue":"5","key":"pgen.1011212.ref007","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/YPG.0000000000000206","article-title":"Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia","volume":"28","author":"D. Curtis","year":"2018","journal-title":"Psychiatr Genet"},{"issue":"1","key":"pgen.1011212.ref008","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41588-020-00748-0","article-title":"Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction","volume":"53","author":"DV Conti","year":"2021","journal-title":"Nat Genet"},{"issue":"8","key":"pgen.1011212.ref009","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/ng.3603","article-title":"Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus","volume":"48","author":"DL Morris","year":"2016","journal-title":"Nat Genet"},{"issue":"3","key":"pgen.1011212.ref010","doi-asserted-by":"crossref","first-page":"e1003348","DOI":"10.1371\/journal.pgen.1003348","article-title":"Power and predictive accuracy of polygenic risk scores","volume":"9","author":"F. 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