| Title: | Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1 |
| Journal: | Molecular Psychiatry |
| Published: | 1 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35365809/ |
| DOI: | https://doi.org/10.1038/s41380-022-01526-6 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167722 |
| Citations: | 17 (14 in last 2 years) as of 8 Aug 2024 |
Publication 12441
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Abstract
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-β42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.</p>
8 Keywords
- Alzheimer Disease
- Animals
- Caribbean Region
- Drosophila
- Ethnicity
- Humans
- Polymorphism, Single Nucleotide
- Zebrafish
13 Authors
- Caghan Kizil
- Sanjeev Sariya
- Yoon A. Kim
- Farid Rajabli
- Eden Martin
- Dolly Reyes-Dumeyer
- Badri Vardarajan
- Aleyda Maldonado
- Jonathan L. Haines
- Richard Mayeux
- Ivonne Z. Jiménez-Velázquez
- Ismael Santa-Maria
- Giuseppe Tosto
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