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

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. GreenLisa L. Barnes, Laura B. Cantwell, Daniele 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

Research output: Contribution to journalArticle

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 (0.8-47). 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

Original languageEnglish (US)
Pages (from-to)1483-1492
Number of pages10
JournalJournal of the American Medical Association
Volume309
Issue number14
DOIs
StatePublished - Apr 10 2013

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ATP-Binding Cassette Transporters
Apolipoproteins
African Americans
Alzheimer Disease
Single Nucleotide Polymorphism
Linkage Disequilibrium
Genome
Genes
Genetic Loci
Genetic Testing
Gene Frequency
Meta-Analysis
Odds Ratio
Genotype
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

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Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein e ε4, and the risk of late-onset Alzheimer disease in African Americans. / Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li San; Valladares, Otto; Lin, Chiao Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, Daniele Daniele; Go, Rodney C P; Griffith, Patrick; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Mayeux, Richard.

In: Journal of the American Medical Association, Vol. 309, No. 14, 10.04.2013, p. 1483-1492.

Research output: Contribution to journalArticle

Reitz, C, Jun, G, Naj, A, Rajbhandary, R, Vardarajan, BN, Wang, LS, Valladares, O, Lin, CF, 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, Fallin, DD, Go, RCP, Griffith, P, Obisesan, TO, Manly, JJ, Lunetta, KL, Kamboh, MI, Lopez, OL, Bennett, DA, Hendrie, H, Hall, KS, Goate, AM, Byrd, GS, Kukull, WA, Foroud, TM, Haines, JL, Farrer, LA, Pericak-Vance, MA, Schellenberg, GD & Mayeux, R 2013, 'Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein e ε4, and the risk of late-onset Alzheimer disease in African Americans', Journal of the American Medical Association, vol. 309, no. 14, pp. 1483-1492. https://doi.org/10.1001/jama.2013.2973
Reitz, Christiane ; Jun, Gyungah ; Naj, Adam ; Rajbhandary, Ruchita ; Vardarajan, Badri Narayan ; Wang, Li San ; Valladares, Otto ; Lin, Chiao Feng ; Larson, Eric B. ; Graff-Radford, Neill R. ; Evans, Denis ; De Jager, Philip L. ; Crane, Paul K. ; Buxbaum, Joseph D. ; Murrell, Jill R. ; Raj, Towfique ; Ertekin-Taner, Nilufer ; Logue, Mark ; Baldwin, Clinton T. ; Green, Robert C. ; Barnes, Lisa L. ; Cantwell, Laura B. ; Fallin, Daniele Daniele ; Go, Rodney C P ; Griffith, Patrick ; Obisesan, Thomas O. ; Manly, Jennifer J. ; Lunetta, Kathryn L. ; Kamboh, M. Ilyas ; Lopez, Oscar L. ; Bennett, David A. ; Hendrie, Hugh ; Hall, Kathleen S. ; Goate, Alison M. ; Byrd, Goldie S. ; Kukull, Walter A. ; Foroud, Tatiana M. ; Haines, Jonathan L. ; Farrer, Lindsay A. ; Pericak-Vance, Margaret A. ; Schellenberg, Gerard D. ; Mayeux, Richard. / Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein e ε4, and the risk of late-onset Alzheimer disease in African Americans. In: Journal of the American Medical Association. 2013 ; Vol. 309, No. 14. pp. 1483-1492.
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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 (0.8-47). 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",
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T1 - Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein e ε4, and the risk of late-onset Alzheimer disease in African Americans

AU - Reitz, Christiane

AU - Jun, Gyungah

AU - Naj, Adam

AU - Rajbhandary, Ruchita

AU - Vardarajan, Badri Narayan

AU - Wang, Li San

AU - Valladares, Otto

AU - Lin, Chiao Feng

AU - Larson, Eric B.

AU - Graff-Radford, Neill R.

AU - Evans, Denis

AU - De Jager, Philip L.

AU - Crane, Paul K.

AU - Buxbaum, Joseph D.

AU - Murrell, Jill R.

AU - Raj, Towfique

AU - Ertekin-Taner, Nilufer

AU - Logue, Mark

AU - Baldwin, Clinton T.

AU - Green, Robert C.

AU - Barnes, Lisa L.

AU - Cantwell, Laura B.

AU - Fallin, Daniele Daniele

AU - Go, Rodney C P

AU - Griffith, Patrick

AU - Obisesan, Thomas O.

AU - Manly, Jennifer J.

AU - Lunetta, Kathryn L.

AU - Kamboh, M. Ilyas

AU - Lopez, Oscar L.

AU - Bennett, David A.

AU - Hendrie, Hugh

AU - Hall, Kathleen S.

AU - Goate, Alison M.

AU - Byrd, Goldie S.

AU - Kukull, Walter A.

AU - Foroud, Tatiana M.

AU - Haines, Jonathan L.

AU - Farrer, Lindsay A.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard D.

AU - Mayeux, Richard

PY - 2013/4/10

Y1 - 2013/4/10

N2 - 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 (0.8-47). 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

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