Language
English
Publication Date
7-17-2025
Journal
Genome Biology
DOI
10.1186/s13059-025-03564-z
PMID
40676597
PMCID
PMC12273372
PubMedCentral® Posted Date
7-17-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.
Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14).
Conclusions: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.
Keywords
Humans, Male, Alzheimer Disease, Black or African American, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino, Polymorphism, Single Nucleotide, White, Genome-wide association study (GWAS). GWAS meta-analysis, . Alzheimer disease. Multi-ancestry. Population-specific
Published Open-Access
yes
Recommended Citation
Rajabli, Farid; Benchek, Penelope; Tosto, Giuseppe; et al., "Multi-Ancestry Genome-Wide Meta-Analysis of 56,241 Individuals Identifies Known and Novel Cross-Population and Ancestry-Specific Associations as Novel Risk Loci for Alzheimer’s Disease" (2025). Faculty, Staff and Students Publications. 5280.
https://digitalcommons.library.tmc.edu/baylor_docs/5280