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

Authors

• 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

Recommended Citation

Rajabli, Farid; Benchek, Penelope; Tosto, Giuseppe; Kushch, Nicholas; Sha, Jin; Bazemore, Katrina; Zhu, Congcong; Lee, Wan-Ping; Haut, Jacob; Hamilton-Nelson, Kara L.; Wheeler, Nicholas R.; Zhao, Yi; Farrell, John J.; Grunin, Michelle A.; Leung, Yuk Yee; Kuksa, Pavel P.; Li, Donghe; da Fonseca, Eder Lucio; Mez, Jesse B.; Palmer, Ellen L.; Pillai, Jagan; Sherva, Richard M.; Song, Yeunjoo E.; Zhang, Xiaoling; Ikeuchi, Takeshi; Iqbal, Taha; Pathak, Omkar; Valladares, Otto; Reyes-Dumeyer, Dolly; Kuzma, Amanda B.; and Abner, Erin, "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). Neurology. 2036.
https://scholar.barrowneuro.org/neurology/2036