Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk

Timothy J Hohman; Jessica N Cooke-Bailey; Christiane Reitz; Gyungah Jun; Adam Naj; Gary W Beecham; Zhi Liu; Regina M Carney; Jeffrey M Vance; Michael L Cuccaro; Ruchita Rajbhandary; Badri Narayan Vardarajan; Li-San Wang; Otto Valladares; Chiao-Feng Lin; Eric B Larson; Neill R Graff-Radford; Denis Evans; Philip L De Jager; Paul K Crane; Joseph D Buxbaum; Jill R Murrell; Towfique Raj; Nilufer Ertekin-Taner; Mark W Logue; Clinton T Baldwin; Robert C Green; Lisa L Barnes; Laura B Cantwell; M Daniele Fallin; Rodney C P Go; Patrick Griffith; Thomas O Obisesan; Jennifer J Manly; Kathryn L Lunetta; M Ilyas Kamboh; Oscar L Lopez; David A Bennett; John Hardy; Hugh C Hendrie; Kathleen S Hall; Alison M Goate; Rosalyn Lang; Goldie S Byrd; Walter A Kukull; Tatiana M Foroud; Lindsay A Farrer; Eden R Martin; Margaret A Pericak-Vance; Gerard D Schellenberg; Richard Mayeux; Jonathan L Haines; Tricia A Thornton-Wells; Alzheimer Disease Genetics Consortium

doi:10.1016/j.jalz.2015.02.012

Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk

Alzheimers Dement. 2016 Mar;12(3):233-43. doi: 10.1016/j.jalz.2015.02.012. Epub 2015 Jun 16.

Authors

Timothy J Hohman¹, Jessica N Cooke-Bailey¹, Christiane Reitz², Gyungah Jun³, Adam Naj⁴, Gary W Beecham⁵, Zhi Liu⁵, Regina M Carney⁶, Jeffrey M Vance⁷, Michael L Cuccaro⁸, Ruchita Rajbhandary⁵, Badri Narayan Vardarajan², Li-San Wang⁹, Otto Valladares⁹, Chiao-Feng Lin⁹, Eric B Larson¹⁰, Neill R Graff-Radford¹¹, Denis Evans¹², Philip L De Jager¹³, Paul K Crane¹⁰, Joseph D Buxbaum¹⁴, Jill R Murrell¹⁵, Towfique Raj¹³, Nilufer Ertekin-Taner¹¹, Mark W Logue¹⁶, Clinton T Baldwin¹⁷, Robert C Green¹⁸, Lisa L Barnes¹⁹, Laura B Cantwell⁹, M Daniele Fallin²⁰, Rodney C P Go²¹, Patrick Griffith²², Thomas O Obisesan²³, Jennifer J Manly², Kathryn L Lunetta²⁴, M Ilyas Kamboh²⁵, Oscar L Lopez²⁵, David A Bennett²⁶, John Hardy²⁷, Hugh C Hendrie²⁸, Kathleen S Hall²⁸, Alison M Goate²⁹, Rosalyn Lang³⁰, Goldie S Byrd³⁰, Walter A Kukull³¹, Tatiana M Foroud³², Lindsay A Farrer³³, Eden R Martin³⁴, Margaret A Pericak-Vance⁷, Gerard D Schellenberg⁹, Richard Mayeux², Jonathan L Haines¹, Tricia A Thornton-Wells³⁵; Alzheimer Disease Genetics Consortium

Affiliations

¹ Center for Human Genetics and Research, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
² Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁴ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
⁶ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Psychiatry & Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA.
⁷ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
⁸ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Psychology, College of Arts & Sciences, University of Miami, Miami, FL, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA; Group Health Research Institute, Group Health, Seattle, WA, USA.
¹¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
¹² Department of Internal Medicine, Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, USA.
¹³ Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, The Broad Institute, Cambridge, MA, USA.
¹⁴ Department of Psychiatry, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA; Department of Genetics and Genomic Sciences, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA; Department of Neuroscience, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA.
¹⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁶ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁷ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
¹⁸ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²⁰ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
²¹ School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²² Division of Neurology, Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA.
²³ Division of Geriatrics, Howard University Hospital, Washington, DC, USA.
²⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁵ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA.
²⁶ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁷ Department of Molecular Neuroscience, Institute of Neurology, University College of London, London, UK.
²⁸ Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA.
³⁰ Department of Biology, North Carolina A & T State University, Greensboro, NC, USA.
³¹ National Alzheimer's Coordinating Center and Department of Epidemiology, University of Washington, Seattle, WA, USA.
³² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³³ Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA; Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
³⁴ Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA.
³⁵ Center for Human Genetics and Research, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address: t.thornton-wells@vanderbilt.edu.

Abstract

Introduction: African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.

Methods: We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.

Results: Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.

Discussion: Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Keywords: Admixture mapping; African-American; Alzheimer's disease; Genome-wide association analysis (GWAS); Local admixture; Local ancestry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ATP-Binding Cassette Transporters / genetics
Aged
Aged, 80 and over
Alzheimer Disease / epidemiology
Alzheimer Disease / ethnology*
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Black or African American / genetics
Chi-Square Distribution
Chromosome Aberrations
Cohort Studies
Female
Genetic Association Studies
Genetic Predisposition to Disease / genetics*
Genotype
Humans
Male
Polymorphism, Single Nucleotide / genetics
Sialic Acid Binding Ig-like Lectin 3 / genetics

Substances

ABCA7 protein, human
ATP-Binding Cassette Transporters
Apolipoproteins E
Sialic Acid Binding Ig-like Lectin 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding