Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias

CA Ellis; KL Oliver; RV Harris; R Ottman; IE Scheffer; HC Mefford; MP Epstein; SF Berkovic; M Bahlo

Journal article

Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias

CA Ellis, KL Oliver, RV Harris, R Ottman, IE Scheffer, HC Mefford, MP Epstein, SF Berkovic, M Bahlo

American Journal of Human Genetics | CELL PRESS | Published : 2024

DOI: 10.1016/j.ajhg.2024.07.014

Abstract

Polygenic risk scores (PRSs) are an important tool for understanding the role of common genetic variants in human disease. Standard best practices recommend that PRSs be analyzed in cohorts that are independent of the genome-wide association study (GWAS) used to derive the scores without sample overlap or relatedness between the two cohorts. However, identifying sample overlap and relatedness can be challenging in an era of GWASs performed by large biobanks and international research consortia. Although most genomics researchers are aware of best practices and theoretical concerns about sample overlap and relatedness between GWAS and PRS cohorts, the prevailing assumption is that the risk of..

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University of Melbourne Researchers

Karen L Oliver Author

Rebekah Harris Author

Ingrid Scheffer Author

Sam Berkovic Author

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Grants

Funding Acknowledgements

C.A.E. was supported by the National Insti-tute of Neurological Disorders and Stroke of the National Institutes of Health Award number K23NS121520. S.F.B. and I.E.S. were supported by a National Health and Medical Research Council (NHMRC) of Australia Program grant (1091593) . S.F.B. was supported by an NHMRC Investigator grant (APP1196637) . I.E.S. was supported by an NHMRC Practitioner Fellowship (1006110) and Senior Investigator grant (1172897) . M.B. was supported by an NHMRC Investigator grant (APP1195236) . K.L.O. was supported by an Australian Government Research Training Program Scholarship (APP533086) provided by the Australian Commonwealth Government and the University of Melbourne.