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 Taner, Mark Logue, Clinton T. Baldwin, Robert C. GreenLisa 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

Research output: Contribution to journalArticle

187 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1483-1492
Number of pages10
JournalJAMA - Journal 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
Gene Frequency
Genes
Meta-Analysis
Odds Ratio
Genetic Loci
Genetic Testing
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; Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. 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: JAMA - 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, Taner, N, Logue, M, Baldwin, CT, Green, RC, Barnes, LL, Cantwell, LB, Fallin, MD, 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', JAMA - 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 ; Taner, Nilufer ; Logue, Mark ; Baldwin, Clinton T. ; Green, Robert C. ; Barnes, Lisa L. ; Cantwell, Laura B. ; Fallin, M. 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: JAMA - Journal of the American Medical Association. 2013 ; Vol. 309, No. 14. pp. 1483-1492.
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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 - Taner, Nilufer

AU - Logue, Mark

AU - Baldwin, Clinton T.

AU - Green, Robert C.

AU - Barnes, Lisa L.

AU - Cantwell, Laura B.

AU - Fallin, M. 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<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

AB - 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

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