Summarizing polygenic risks for complex diseases in a clinical whole-genome report.

Ignaty Leshchiner, Joel Krier, David W Bates (Collaborator), Alexis D Carere (Collaborator), Allison Cirino (Collaborator), Lauren Connor (Collaborator), Kurt D Christensen (Collaborator), Jake Duggan (Collaborator), Robert C Green (Collaborator), Carolyn Y Ho (Collaborator), Joel B Krier (Collaborator), William J Lane (Collaborator), Denise M Lautenbach (Collaborator), Lisa Lehmann (Collaborator), Christina Liu (Collaborator), Calum A MacRae (Collaborator), Rachel Miller (Collaborator), Cynthia C Morton (Collaborator), Christine E Seidman (Collaborator), Shamil Sunyaev (Collaborator)Jason L Vassy (Collaborator), Sandy Aronson (Collaborator), Ozge Ceyhan-Birsoy (Collaborator), Siva Gowrisankar (Collaborator), Matthew S Lebo (Collaborator), Ignat Leschiner (Collaborator), Kalotina Machini (Collaborator), Heather M McLaughlin (Collaborator), Danielle R Metterville (Collaborator), Heidi L Rehm (Collaborator), Jennifer Blumenthal-Barby (Collaborator), Lindsay Zausmer Feuerman (Collaborator), Amy L McGuire (Collaborator), Sarita Panchang (Collaborator), Jill Oliver Robinson (Collaborator), Melody J Slashinski (Collaborator), Stewart C Alexander (Collaborator), Kelly Davis (Collaborator), Peter A Ubel (Collaborator), Peter Kraft (Collaborator), J Scott Roberts (Collaborator), Judy E Garber (Collaborator), Tina Hambuch (Collaborator), Michael F Murray (Collaborator), Isaac S Kohane (Collaborator), Sek Won Kong (Collaborator), In-Hee Lee (Collaborator)

    Research output: Contribution to journalArticlepeer-review


    PURPOSE: Disease-causing mutations and pharmacogenomic variants are of primary interest for clinical whole-genome sequencing. However, estimating genetic liability for common complex diseases using established risk alleles might one day prove clinically useful. METHODS: We compared polygenic scoring methods using a case-control data set with independently discovered risk alleles in the MedSeq Project. For eight traits of clinical relevance in both the primary-care and cardiomyopathy study cohorts, we estimated multiplicative polygenic risk scores using 161 published risk alleles and then normalized them using the population median estimated from the 1000 Genomes Project. RESULTS: Our polygenic score approach identified the overrepresentation of independently discovered risk alleles in cases as compared with controls using a large-scale genome-wide association study data set. In addition to normalized multiplicative polygenic risk scores and rank in a population, the disease prevalence and proportion of heritability explained by known common risk variants provide important context in the interpretation of modern multilocus disease risk models. CONCLUSION: Our approach in the MedSeq Project demonstrates how complex trait risk variants from an individual genome can be summarized and reported for the general clinician and also highlights the need for definitive clinical studies to obtain reference data for such estimates and to establish clinical utility.
    Original languageEnglish
    JournalGenetics in medicine : official journal of the American College of Medical Genetics
    Issue number7
    Publication statusPublished - Jul 2015


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