Polygenic resilience scores capture protective genetic effects for Alzheimer's disease.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
25 07 2022
25 07 2022
Historique:
received:
16
06
2022
accepted:
01
07
2022
revised:
23
06
2022
entrez:
25
7
2022
pubmed:
26
7
2022
medline:
28
7
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35879306
doi: 10.1038/s41398-022-02055-0
pii: 10.1038/s41398-022-02055-0
pmc: PMC9314356
doi:
Substances chimiques
Apolipoprotein E4
0
Apolipoproteins E
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
296Subventions
Organisme : Medical Research Council
ID : MC_PC_17112
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0902227
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01AG054002
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG064955
Pays : United States
Organisme : NIA NIH HHS
ID : R01AG064955
Pays : United States
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300429
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG076838
Pays : United States
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L501517/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T04604X/1
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH116037
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : Medical Research Council
ID : MR/K013041/1
Pays : United Kingdom
Organisme : NIAMS NIH HHS
ID : U01 AR076092
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG050595
Pays : United States
Informations de copyright
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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