Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ϵ4, and the Risk of Late-Onset Alzheimer Disease in African Americans
Year: 2013
Type: article
Study design: Observational Study
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.
Source: JAMA
Authors: Christiane Reitz, Gyungah Jun, Adam Naj, 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 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, Hugh Hendrie, Kathleen S. Hall, Alison M. Goate, Goldie S. Byrd, Walter A. Kukull, Tatiana M. Foroud, Jonathan L. Haines, Lindsay A. Farrer, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Richard Mayeux
Institutions: Columbia University, Boston University, University of Pennsylvania, University of Miami, Group Health Cooperative, University of Washington, Mayo Clinic in Florida, Rush University, Broad Institute, Harvard University, Icahn School of Medicine at Mount Sinai, Indiana University – Purdue University Indianapolis, Johns Hopkins University, University of Alabama at Birmingham, Meharry Medical College, Howard University, University of Pittsburgh, Regenstrief Institute, Indiana University Bloomington, Washington University in St. Louis, North Carolina Agricultural and Technical State University, Vanderbilt University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Alzheimer's Association, Amgen, Pfizer, Eisai, H. Lundbeck A/S, National Institutes of Health, Genentech, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Institute on Minority Health and Health Disparities
Awards: G1044804105, G1104192986, Genome-Wide Association Study of Cognitive Decline Among Older African Americans, Epidemiologic Study of Neural Reserve and Neurobiology of Aging, Interdisciplinary Approach to Alzheimer Drug Discovery, G1151953314, G1282666458, G1322720882, UC Davis Alzheimer's Disease Core Center, Indiana Alzheimer Disease Center, Genetic Studies of Dementia in the Amish, G1462053621, Genetic Epidemiology of Alzheimer's Disease in African Americans, G1591652791, G1627990026, G166202059, G168247613, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, G1833239675, G1845811550, G199972683, G2038718543, G2118367474, G2119737015, Subclinical Hypothyroidism: Mood, Cognition and the effect of L-thyroxine treatme, Epidemiology of Biomarkers of Risk and Progression in LOAD, G2200385677, G2233829795, G24174556, University of Kentucky Alzheimer's Disease Core Center, G249615658, Epidemiology of Dementia In An Urban Community, Neurobiology of Alzheimer's Disease and Aging, G2769554943, G2914006832, G2999798359, Alzheimer's Disease Research Center, G3083277455, ADCC Genomic Medicine Approach to MCI and Dementia, Alzheimer's Disease Patient Registry (ADPR/ACT), National Alzheimer's Coordinating Center, UCSD Alzheimer's Disease Research Center P50, G332781187, G3395865068, Mapping Causative factors in the sortilin-related pathway in Alzheimer's Disease, G3487525919, G3509705169, Alzheimer's Disease Research Center, Clinical Impact of Unstable AED Levels in Elderly Nursing Home Epilepsy Patients, Mayo Clinic Center for Translational Science Activities, UCLA Alzheimer's Disease Research Center, Genomic Convergence in Alzheimer Disease, Risk Factors for Incident Alzheimer's Disease in a Biracial Community, Imaging and genetic biomarkers for Alzheimer's disease, Institutional Clinical and Translational Science Award, ALZHEIMER'S DISEASE RESEARCH CENTER, Alzheimer's Disease Core Center, The Alzheimer's Disease Research Center at the University of California, Irvine, G4579004003, Alzheimer's Disease and Gene Discovery on Chromosome 9, Search for the Alzheimers Genes, Alzheimer's Disease Cooperative Study (ADCS), Risk Factors, Pathology, and Clinical Expressions of AD, Oregon Alzheimer's Disease Center, Rush Alzheimer's Disease Core Center, Molecular and Genetic Epidemiology of Autism, Alzheimer's Disease Genetics Consortium, GENETIC EPIDEMIOLOGY OF ALZHEIMERS DISEASE IN HISPANICS, G561739401, Brain Imaging, APOE & the Preclinical Course of Alzheimer's Disease, General Clinical Research Center, Alzheimer's Disease Core Center, Epidemiology of Familial Late-Onset Alzheimer's Disease, ALZHEIMER'S DISEASE RESEARCH CENTER, Alzheimer's Disease Research Center - Overall, Development and Use of Network Infrastructure for High-Throughput GWA Studies, Genetic Discovery and Application in a Clinical Setting Continuing a Partnership, G6648385527, G6773656114, Alzheimer's Disease Research Center, Alzheimer Disease Research Center, Epigenomics of Alzheimer's Disease, Genome wide association study of gene expression levels in Alzheimer's disease, Michigan Alzheimer's Disease Research Center, Arizona Alzheimer's Disease Core Center, Genetic Associations with Alzheimer-free Survival, Johns Hopkins Alzheimer's Disease Research Center, G710411779, Healthy Aging and Senile Dementia, Genetic Consortium for Late Onset Alzheimer's Disease, Boston University Alzheimer's Disease Center, Alzheimer's Disease Research Center, Massachusetts Alzheimer's Disease Research Center, Alzheimer's Disease Core Center, Alzheimer's Disease Cooperative Study, An Integrated Genomic Approach to Alzheimer Disease, Multi-ethnic Genome-wide Alzheimer association study, Expanding Research and Research Training Infrastructure at NCA&TSU, Emory Alzheimer's Disease Center, Genetic Epidemiological Studies of Alzheimer Disease, G821305511, Genetics of Alzheimer's Disease in Israeli Arabs, Genome Wide associate analysis of Alzheimer's Disease, AD Gene Discovery: Exome Chip, New Endophenotypes & Functional Studies in CHARGE, Clinical and Biological Studies of Early AD, The Genetics of Parkinsonism, G859153142, Conte Centers for the Neuroscience of Depression, Genetic Epidemiology of Alzheimer's Disease in Hispanics, Older Breast Cancer Patients: Risk For Cognitive Decline, National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS), Frontotemporal Dementia: Genes, Images, and Emotions, Racial Differences in Late-Life Cognitive decline and risk of Alzheimer's Disease, 2/2 CCNY-MSKCC Partnership for Cancer Research, Education and Community Outreach, Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), Massachusetts Alzheimer's Disease Research Center (MADRC), 1/2 CCNY-MSK Partnership for Cancer Research, Education and Community Outreach, New Approaches to Dementia Heterogeneity, G919295597, Genetic Risk Factors for Alzheimers Disease, G931319380, G955521001, Mayo Alzheimer's Disease Research Center, Indianapolis-Ibadan Dementia Project
OpenAlex ID: W2003958717