Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

TitleVariants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.
Publication TypeJournal Article
Year of Publication2013
AuthorsReitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BNarayan, San Wang L-, Otto Valladares, Lin C-F, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, M Fallin D, Go RCP, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, M Kamboh I, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Walter A Kukull, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Gerard D Schellenberg, Mayeux R
Corporate AuthorsAlzheimer Disease Genetics Consortium
JournalJAMA
Volume309
Issue14
Pagination1483-92
Date Published2013 Apr 10
ISSN1538-3598
KeywordsAfrican Americans, Age of Onset, Aged, Alzheimer Disease, Apolipoprotein E4, ATP-Binding Cassette Transporters, Case-Control Studies, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Polymorphism, Single Nucleotide, Risk
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.

DOI10.1001/jama.2013.2973
Alternate JournalJAMA
PubMed ID23571587
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