Affiliation:
1. Taub Institute for Research on Alzheimer's Disease and the Aging Brain Columbia University New York New York USA
2. The John P. Hussman Institute for Human Genomics University of Miami Miami Florida USA
3. German Center for Neurodegenerative Diseases Dresden Germany
4. Penn Neurodegeneration Genomics Center Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania USA
5. Department of Biostatistics and Health Data Science Indiana University School of Medicine Indianapolis Indiana USA
6. Department of Psychiatry Indiana University School of Medicine Indianapolis Indiana USA
7. College of Medicine University of Ibadan Ibadan Oyo Nigeria
8. Dr. John T. MacDonald Foundation Department of Human Genetics University of Miami Miami Florida USA
9. Department of Genetics and Genome Sciences School of Medicine Case Western Reserve University Biomedical Research Cleveland Ohio USA
10. Department of Population and Quantitative Health Sciences and Cleveland Institute for Computational Biology School of Medicine Case Western Reserve University Cleveland Ohio USA
11. Department of Medicine Biomedical Genetics Section Boston University School of Medicine Boston Massachusetts USA
12. Department of Neurology Boston University School of Medicine Boston Massachusetts USA
13. Department of Biostatistics Boston University School of Public Health Boston Massachusetts USA
14. Department of Ophthalmology Boston University School of Medicine Boston Massachusetts USA
15. Department of Epidemiology Boston University School of Public Health Boston Massachusetts USA
16. Maya Angelou Center for Health Equity Wake Forest School of Medicine Winston‐Salem North Carolina USA
17. Gertrude H. Sergievsky Center Columbia University New York New York USA
18. Department of Neurology Columbia University New York New York USA
19. Department of Psychiatry Columbia University New York New York USA
20. Epidemiology, College of Physicians and Surgeons Columbia University New York New York USA
Abstract
AbstractINTRODUCTIONDespite a two‐fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts.METHODSGenome‐wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within‐dataset results were meta‐analyzed, followed by functional genomics analyses.RESULTSA novel AD‐risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10−9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10−7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry.DISCUSSIONThese analyses identified novel AD‐associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects.Highlights
Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies.
The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa.
Single variant meta‐analysis identified a novel genome‐wide significant AD‐risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome‐wide significance at p < 9×10−7.
Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus.
These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry‐informed genetic screening tools and therapeutic interventions.
Funder
National Institutes of Health
University of Pennsylvania
National Association for Colitis and Crohn's Disease
Boston University
Columbia University
Duke University
Emory University
Indiana University
Johns Hopkins University
Massachusetts General Hospital
Mayo Clinic
New York University
Northwestern University
Oregon Health and Science University
Rush University
National Institute on Aging
University of Alabama at Birmingham
University of Arizona
University of California, Davis
University of California, Irvine
University of California, Los Angeles
University of California, San Diego
University of California, San Francisco
University of Kentucky
University of Michigan
University of Pittsburgh
University of Southern California
University of Miami
University of Washington
Vanderbilt University
National Institute of Neurological Disorders and Stroke
Alzheimer's Association
Office of Research and Development
BrightFocus Foundation
Wellcome Trust
Howard Hughes Medical Institute
Medical Research Council
Newcastle University
Higher Education Funding Council for England
Alzheimer's Research Trust
BRACE
Stichting MS Research
U.S. Department of Defense
National Institute of Biomedical Imaging and Bioengineering
AbbVie
Alzheimer's Drug Discovery Foundation
BioClinica
Biogen
Bristol-Myers Squibb
Eli Lilly and Company
Genentech
Fujirebio Europe
GE Healthcare
H. Lundbeck A/S
Merck
Novartis Pharmaceuticals Corporation
Pfizer
Servier
Takeda Pharmaceutical Company
Illinois Department of Public Health
Translational Genomics Research Institute