Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
04
10
2021
accepted:
14
03
2022
revised:
28
02
2022
pubmed:
3
4
2022
medline:
3
6
2022
entrez:
2
4
2022
Statut:
ppublish
Résumé
Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-β
Identifiants
pubmed: 35365809
doi: 10.1038/s41380-022-01526-6
pii: 10.1038/s41380-022-01526-6
pmc: PMC9167722
mid: NIHMS1789202
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2813-2820Subventions
Organisme : NIA NIH HHS
ID : R56 AG066889
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG069118
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R21 AG054832
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067501
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG059756
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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