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Aging"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer\u2019s disease (LOAD) beyond apolipoprotein E (\n                    <jats:italic>APOE)<\/jats:italic>\n                    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\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast \u201cresilient\u201d 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.\n                  <\/jats:p>","DOI":"10.1038\/s41398-022-02055-0","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T09:03:29Z","timestamp":1658739809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Polygenic resilience scores capture protective genetic effects for Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"12","author":[{"given":"Jiahui","family":"Hou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8406-632X","authenticated-orcid":false,"given":"Jonathan 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SVF in the past year, received income, potential income, travel expenses continuing education support and\/or research support from Aardvark, Akili, Genomind, Ironshore, KemPharm\/Corium, Noven, Ondosis, Otsuka, Rhodes, Supernus, Takeda, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, Arbor, Aveksham, CogCubed, Eli Lilly, Enzymotec, Impact, Janssen, Lundbeck\/Takeda, McNeil, NeuroLifeSciences, Neurovance, Novartis, Pfizer, Shire, and Sunovion. He also receives royalties from books published by Guilford Press: <i>Straight Talk about Your Child\u2019s Mental Health<\/i>; Oxford University Press: <i>Schizophrenia: The Facts;<\/i> and Elsevier: <i>ADHD: Non-Pharmacologic Interventions<\/i>. He is also Program Director of\n                      \n                      . He is supported by the European Union\u2019s Horizon 2020 research and innovation programme under grant agreement No 965381; NIMH grants U01AR076092-01A1, 1R21MH1264940, R01MH116037; Oregon Health and Science University, Otsuka Pharmaceuticals, Noven Pharmaceuticals Incorporated, and Supernus Pharmaceutical Company. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"296"}}