Journal Article

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

Schneider, Julie A., Kramer, Joel H., Beekly, Duane, Cuccaro, Michael L., Trojanowski, John Q., Harrell, Lindy E., Mains, Douglas, Kikuchi, Masataka, Ory, Marcia, George-Hyslop, Peter St, Seeley, William W., Apostolova, Liana G., Duara, Ranjan, Royall, Donald R., Benitez, Bruno A., Frosch, Matthew P., Rajabli, Farid, Margaret, Flanagan E., Myers, Amanda J., Weintraub, Sandra, Spina, Salvatore, Atwood, Craig S., Barber, Robert C., Johnson, Leigh, Bennett, David, Reisch, Joan S., Welsh-Bohmer, Kathleen A., Reyes-Dumeyer, Dolly, Buxbaum, Joseph D., Adams, Larry D., Carney, Regina M., Byrd, Goldie S., Huentelman, Matthew J., Chasse, Scott, Cullum, Munro, Vassar, Robert, Dickson, Dennis W., Paydarfar, David, Allen, Mariet, Hamilton, Ronald L., Chung, Jaeyoon, Paulson, Henry L., Monuki, Edwin S., Davis, Barbara, Hakonarson, Hakon, Katz, Mindy J., Nguyen, Trung, Go, Rodney C.P., Baldwin, Clinton T., Kushch, Nicholas, Chui, Helena C., Kowall, Neil W., Lunetta, Kathryn L., Woltjer, Randall L., Quiceno, Mary, Sultzer, David, Farrell, John J., Perez, Victoria, Green, Robert C., Pavlik, Valory, Sha, Jin, Pathak, Omka

2025

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Alzheimer disease / Alzheimer Disease - ethnology / Alzheimer Disease - genetics / Alzheimer's disease / Amyloid / ancestry / Animal Genetics and Genomics / Apolipoprotein E / Bioinformatics / Biomedical and Life Sciences / Black or African American - genetics / complement / data collection / Datasets / Dementia / Evolutionary Biology / Gene loci / Genetic Loci / Genetic Predisposition to Disease / genome / Genome-wide association studies / Genome-Wide Association Study / Genome-wide association study (GWAS) / Genomes / Genomic analysis / genomics / GWAS meta-analysis / Health risk assessment / Hispanic Americans / Hispanic or Latino - genetics / Human Genetics / Humans / Insights from trans-ancestral association study / insulin receptors / Life Sciences / loci / Male / Meta-analysis / Microbial Genetics and Genomics / Multi-ancestry / Neurodegenerative diseases / neurons / Pathology / Plant Genetics and Genomics / Polymorphism, Single Nucleotide / Population / Population-specific / Precision medicine / risk / sample size / White - genetics