Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease
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Published:2022-07-25
Issue:1
Volume:12
Page:
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ISSN:2158-3188
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Container-title:Translational Psychiatry
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language:en
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Short-container-title:Transl Psychiatry
Author:
Hou Jiahui, Hess Jonathan L.ORCID, Armstrong Nicola, Bis Joshua C.ORCID, Grenier-Boley Benjamin, Karlsson Ida K., Leonenko Ganna, Numbers Katya, O’Brien Eleanor K., Shadrin AlexeyORCID, Thalamuthu Anbupalam, Yang QiongORCID, Andreassen Ole A.ORCID, Brodaty HenryORCID, Gatz MargaretORCID, Kochan Nicole A., Lambert Jean-CharlesORCID, Laws Simon M.ORCID, Masters Colin L., Mather Karen A.ORCID, Pedersen Nancy L., Posthuma DanielleORCID, Sachdev Perminder S.ORCID, Williams JulieORCID, Fan Chun ChiehORCID, Faraone Stephen V., Fennema-Notestine Christine, Lin Shu-Ju, Escott-Price ValentinaORCID, Holmans PeterORCID, Seshadri Sudha, Tsuang Ming T.ORCID, Kremen William S., Glatt Stephen J.ORCID,
Abstract
AbstractPolygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer’s disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast “resilient” unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.
Funder
U.S. Department of Health & Human Services | NIH | National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health
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