Extended genome‐wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry

Author:

Ray Nicholas R.1,Kunkle Brian W.2,Hamilton‐Nelson Kara2,Kurup Jiji T.1,Rajabli Farid2,Qiao Min1,Vardarajan Badri N.1,Cosacak Mehmet I.3,Kizil Caghan1,Jean‐Francois Melissa2,Cuccaro Michael2,Reyes‐Dumeyer Dolly1,Cantwell Laura4,Kuzma Amanda4,Vance Jeffery M.2,Gao Sujuan5,Hendrie Hugh C.6,Baiyewu Olusegun7,Ogunniyi Adesola7,Akinyemi Rufus O.7, ,Lee Wan‐Ping4,Martin Eden R.28,Wang Li‐San4,Beecham Gary W.2,Bush William S.910,Xu Wanying9,Jin Fulai910,Wang Liyong2,Farrer Lindsay A.1112131415,Haines Jonathan L.10,Byrd Goldie S.16,Schellenberg Gerard D.4,Mayeux Richard117181920,Pericak‐Vance Margaret A.28,Reitz Christiane1171820

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 (< 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

Publisher

Wiley

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