TY - JOUR
T1 - Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease
AU - the Alzheimer’s Disease Neuroimaging Initiative
AU - Hou, Jiahui
AU - Hess, Jonathan L.
AU - Armstrong, Nicola
AU - Bis, Joshua C.
AU - Grenier-Boley, Benjamin
AU - Karlsson, Ida K.
AU - Leonenko, Ganna
AU - Numbers, Katya
AU - O’Brien, Eleanor K.
AU - Shadrin, Alexey
AU - Thalamuthu, Anbupalam
AU - Yang, Qiong
AU - Andreassen, Ole A.
AU - Brodaty, Henry
AU - Gatz, Margaret
AU - Kochan, Nicole A.
AU - Lambert, Jean Charles
AU - Laws, Simon M.
AU - Masters, Colin L.
AU - Mather, Karen A.
AU - Pedersen, Nancy L.
AU - Posthuma, Danielle
AU - Sachdev, Perminder S.
AU - Williams, Julie
AU - Fan, Chun Chieh
AU - Faraone, Stephen V.
AU - Fennema-Notestine, Christine
AU - Lin, Shu Ju
AU - Escott-Price, Valentina
AU - Holmans, Peter
AU - Seshadri, Sudha
AU - Tsuang, Ming T.
AU - Kremen, William S.
AU - Glatt, Stephen J.
N1 - Funding Information:
OAA is a consultant to HealthLytix. 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: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also Program Director of www.adhdinadults.com . He is supported by the European Union’s 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.
Funding Information:
We thank all the participants of this study for their contributions. Our effort on this project was supported by the U.S. National Institute on Aging [grant numbers R01AG064955 and R01AG054002]. Additional acknowledgements and detailed acknowledgements of funding sources for the study are provided in Supplementary acknowledgements.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - Polygenic 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.
AB - Polygenic 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.
UR - http://www.scopus.com/inward/record.url?scp=85134766683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134766683&partnerID=8YFLogxK
U2 - 10.1038/s41398-022-02055-0
DO - 10.1038/s41398-022-02055-0
M3 - Article
C2 - 35879306
AN - SCOPUS:85134766683
SN - 2158-3188
VL - 12
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 296
ER -