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Original Contribution
April 10, 2013

Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ϵ4, and the Risk of Late-Onset Alzheimer Disease in African Americans

Author Affiliations

Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Reitz, Manly, and Mayeux), Gertrude H. Sergievsky Center (Drs Reitz and Mayeux), and Departments of Neurology (Drs Reitz, Manly, and Mayeux), Psychiatry (Dr Mayeux), and Epidemiology (Dr Mayeux), College of Physicians and Surgeons, Columbia University, New York, New York; Departments of Medicine (Genetics Program) (Drs Jun, Vardarajan, Logue, Baldwin, and Farrer), Biostatistics (Drs Jun, Vardarajan, Lunetta, and Farrer), Ophthalmology (Drs Jun and Farrer), Epidemiology (Dr Farrer), and Neurology (Dr Farrer), Boston University, Boston, Massachusetts; The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida (Drs Naj and Pericak-Vance and Ms Rajbhandary); Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (Drs Wang, Lin, and Schellenberg and Mr Valladares and Ms Cantwell); Department of Medicine (Drs Larson and Crane) and National Alzheimer's Coordinating Center and Department of Epidemiology (Dr Kukull), University of Washington, Seattle; Group Health Research Institute, Group Health, Seattle (Dr Larson); Departments of Neuroscience (Drs Graff-Radford, and Ertekin- Taner) and Neurology (Drs Graff-Radford and Ertekin- Taner), Mayo Clinic, Jacksonville, Florida; Rush Institute for Healthy Aging, Department of Internal Medicine (Dr Evans), Departments of Neurological Sciences (Drs Barnes and Bennett) and Behavioral Sciences (Dr Barnes), and Rush Alzheimer's Disease Center (Dr Bennett), Rush University Medical Center, Chicago, Illinois; Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston, Massachusetts (Dr De Jager); Harvard Medical School, Boston (Drs De Jager and Raj); Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts (Dr De Jager); Department of Medical and Molecular Genetics, Indiana University (Drs Murrell and Foroud), Indiana University Center for Aging Research (Dr Hendrie), and Department of Psychiatry, Indiana University School of Medicine (Drs Hendrie and Hall), Indianapolis; Division of Genetics, Department of Medicine, and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (Dr Green); Departments of Psychiatry (Dr Buxbaum), Genetics and Genomics Sciences (Dr Buxbaum), and Neuroscience (Dr Buxbaum) and the Friedman Brain Institute (Dr Buxbaum), Mount Sinai School of Medicine, New York, New York; Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland (Dr Fallin); School of Public Health, University of Alabama at Birmingham (Dr Go); Department of Neurology, Meharry Medical College, Nashville, Tennessee (Dr Griffith); Division of Geriatrics, Howard University Hospital, Washington, DC (Dr Obisesan); Department of Human Genetics (Dr Kamboh) and Alzheimer's Disease Research Center (Drs Kamboh and Lopez), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, Missouri (Dr Goate); Department of Biology, North Carolina A & T University, Winston-Salem (Dr Byrd); Department of Molecular Physiology and Biophysics and Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville (Dr Haines); and Regenstrief Institute Inc, Indianapolis (Dr Hendrie).

JAMA. 2013;309(14):1483-1492. doi:10.1001/jama.2013.2973
Abstract

Importance Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.

Objective To identify genetic loci associated with late-onset Alzheimer disease in African Americans.

Design, Setting, and Participants The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.

Main Outcomes and Measures Presence of Alzheimer disease according to standardized criteria.

Results Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10−9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8<D′<0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4–determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10−47). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005<empirical P < .001).

Conclusions and Relevance In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.

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