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Inflation of polygenic risk scores caused by sample overlap and relatedness: Examples of a major risk of bias.
Ellis, Colin A; Oliver, Karen L; Harris, Rebekah V; Ottman, Ruth; Scheffer, Ingrid E; Mefford, Heather C; Epstein, Michael P; Berkovic, Samuel F; Bahlo, Melanie.
Afiliación
  • Ellis CA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Oliver KL; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Me
  • Harris RV; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • Ottman R; Departments of Neurology and Epidemiology, and the Gertrude H. Sergievsky Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Translational Epidemiology and Mental Health Equity, New York State Psychiatric Institute, New York, NY 10032, USA.
  • Scheffer IE; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, VIC 3052, Australia; The Florey Institute and Murdoch Children's Research Institute, Pa
  • Mefford HC; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Epstein MP; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30307, USA.
  • Berkovic SF; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
  • Bahlo M; Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: bahlo@wehi.edu.au.
Am J Hum Genet ; 111(9): 1805-1809, 2024 Sep 05.
Article en En | MEDLINE | ID: mdl-39168121
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 bias is small for very large GWASs. Here, we present two real-world examples demonstrating that sample overlap and relatedness is not a minor or theoretical concern but an important potential source of bias in PRS studies. Using a recently developed statistical adjustment tool, we found that excluding overlapping and related samples was equal to or more powerful than adjusting for overlap bias. Our goal is to make genomics researchers aware of the magnitude of risk of bias from sample overlap and relatedness and to highlight the need for mitigation tools, including independent validation cohorts in PRS studies, continued development of statistical adjustment methods, and tools for researchers to test their cohorts for overlap and relatedness with GWAS cohorts without sharing individual-level data.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sesgo / Predisposición Genética a la Enfermedad / Herencia Multifactorial / Estudio de Asociación del Genoma Completo Límite: Female / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sesgo / Predisposición Genética a la Enfermedad / Herencia Multifactorial / Estudio de Asociación del Genoma Completo Límite: Female / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos