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

Farid Rajabli, Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Penelope Benchek, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Giuseppe Tosto, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center Department of Neurology, Columbia University, New York, NY, USA.
Nicholas Kushch, The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Jin Sha, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Katrina Bazemore, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Congcong Zhu, Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Wan-Ping Lee, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jacob Haut, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Kara L. Hamilton-Nelson, The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Nicholas R. Wheeler, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Yi Zhao, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
John J. Farrell, Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Michelle A. Grunin, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Yuk Yee Leung, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Pavel P. Kuksa, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Donghe Li, Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Eder Lucio da Fonseca, The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Jesse B. Mez, Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Ellen L. Palmer, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Jagan Pillai, Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA.
Richard M. Sherva, Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Yeunjoo E. Song, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Xiaoling Zhang, Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Takeshi Ikeuchi, Molecular Genetics Division, Brain Research Institute, Niigata University, Niigata, Japan.
Taha Iqbal, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Omkar Pathak, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Otto Valladares, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Dolly Reyes-Dumeyer, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center Department of Neurology, Columbia University, New York, NY, USA.
Amanda B. Kuzma, Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Erin Abner, Sanders-Brown Center on Aging, Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY, USA.

Document Type

Article

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.

Medical Subject Headings

Humans; Male; Alzheimer Disease (genetics, ethnology); Black or African American (genetics); Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Hispanic or Latino (genetics); Polymorphism, Single Nucleotide; White (genetics)

Publication Date

7-17-2025

Publication Title

Genome biology

E-ISSN

1474-760X

Volume

26

Issue

1

First Page

210

PubMed ID

40676597

Digital Object Identifier (DOI)

10.1186/s13059-025-03564-z

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