Description

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer’s Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry 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). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P =2.4×10 -8) and GRB14 (P =1.7×10 -8) in HIS), and KIAA0825 (P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4) and the classical complement pathway (P adjusted =1.3×10 -3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Principal Investigators

  • Penelope Benchek — Case Western Reserve University
  • Gyungah R. Jun — Boston University
  • Adam C. Naj — University of Pennsylvania
  • Farid Rajabli — University of Miami
  • Christiane Reitz — Columbia University
  • Gerard Schellenberg — University of Pennsylvania

Funding Sources

U01AG032984, RC2AG036528

Publications

  • Naj AC. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature genetics. 2011 May. PubMed link
  • Kunkle BW. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature genetics. 2019 Mar. PubMed link
  • Rajabli F. 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. Genome biology. 2025 Jul 17. PubMed link