Admixture Mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1

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=8,813) 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(42) 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.