| Title: |
Polygenic resilience scores capture protective genetic effects for Alzheimer’s disease |
| Authors: |
Hou, J; Hess, JL; Armstrong, N; Bis, JC; Grenier-Boley, B; Karlsson, IK; Leonenko, G; Numbers, K; O’Brien, EK; Shadrin, A; Thalamuthu, A; Yang, Q; Andreassen, OA; Brodaty, H; Gatz, M; Kochan, NA; Lambert, JC; Laws, SM; Masters, CL; Mather, KA; Pedersen, NL; Posthuma, D; Sachdev, PS; Williams, J; Fan, CC; Faraone, SV; Fennema-Notestine, C; Lin, SJ; Escott-Price, V; Holmans, P; Seshadri, S; Tsuang, MT; Kremen, WS; Glatt, SJ |
| Source: |
urn:ISSN:2158-3188 ; Translational Psychiatry, 12, 1, 296 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2022 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 5202 Biological Psychology; 3202 Clinical Sciences; 3209 Neurosciences; 52 Psychology; Neurodegenerative; Alzheimer's Disease; Neurosciences; Dementia; Human Genome; Aging; Prevention; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Genetics; Brain Disorders; Acquired Cognitive Impairment; 2.1 Biological and endogenous factors; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors; Alzheimer’s Disease Neuroimaging Initiative; anzsrc-for: 32 Biomedical and Clinical Sciences; anzsrc-for: 5202 Biological Psychology; anzsrc-for: 3202 Clinical Sciences; anzsrc-for: 3209 Neurosciences |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_80935 |
| DOI: |
10.1038/s41398-022-02055-0 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_80935; https://unsworks.unsw.edu.au/bitstreams/998a1824-9989-4147-952a-2747cbddfab9/download; https://doi.org/10.1038/s41398-022-02055-0 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY ; https://creativecommons.org/licenses/by/4.0/ ; CC BY ; free_to_read |
| Accession Number: |
edsbas.A26EB81E |
| Database: |
BASE |