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Polygenic risk scores derived from genome-wide association studies of European populations perform poorly for other ancestral groups. Given the potential for future clinical utility, underperformance of polygenic risk scores in South Asian populations has the potential to reinforce health inequalities. To determine whether European-derived polygenic risk scores underperform at multiple sclerosis prediction in a South Asian-ancestry population compared with a European-ancestry cohort, we used data from two longitudinal genetic cohort studies: Genes &amp; Health (2015\u2013present), a study of \u223c50 000 British\u2013Bangladeshi and British\u2013Pakistani individuals, and UK Biobank (2006\u2013present), which is comprised of \u223c500 000 predominantly White British individuals. We compared individuals with and without multiple sclerosis in both studies (Genes &amp; Health: NCases = 42, NControl = 40 490; UK Biobank: NCases = 2091, NControl = 374 866). Polygenic risk scores were calculated using clumping and thresholding with risk allele effect sizes obtained from the largest multiple sclerosis genome-wide association study to date. Scores were calculated with and without the major histocompatibility complex region, the most influential locus in determining multiple sclerosis risk. Polygenic risk score prediction was evaluated using Nagelkerke\u2019s pseudo-R2 metric adjusted for case ascertainment, age, sex and the first four genetic principal components. We found that, as expected, European-derived polygenic risk scores perform poorly in the Genes &amp; Health cohort, explaining 1.1% (including the major histocompatibility complex) and 1.5% (excluding the major histocompatibility complex) of disease risk. In contrast, multiple sclerosis polygenic risk scores explained 4.8% (including the major histocompatibility complex) and 2.8% (excluding the major histocompatibility complex) of disease risk in European-ancestry UK Biobank participants. These findings suggest that polygenic risk score prediction of multiple sclerosis based on European genome-wide association study results is less accurate in a South Asian population. Genetic studies of ancestrally diverse populations are required to ensure that polygenic risk scores can be useful across ancestries.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad041","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T16:45:51Z","timestamp":1677084351000},"source":"Crossref","is-referenced-by-count":15,"title":["Polygenic risk score prediction of multiple sclerosis in individuals of South Asian ancestry"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6725-5396","authenticated-orcid":false,"given":"Joshua R","family":"Breedon","sequence":"first","affiliation":[{"name":"Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London , London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R","family":"Marshall","sequence":"additional","affiliation":[{"name":"Preventive Neurology Unit, Wolfson Institute of Population Health, 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