Comprehensive search for Alzheimer disease susceptibility loci in the APOE region

Gyungah Jun; Badri N. Vardarajan; Jacqueline Buros; Chang En Yu; Michele V. Hawk; Beth A. Dombroski; Paul K. Crane; Eric B. Larson; Richard Mayeux; Jonathan L. Haines; Kathryn L. Lunetta; Margaret A. Pericak-Vance; Gerard D. Schellenberg; Lindsay A. Farrer

doi:10.1001/archneurol.2012.2052

Comprehensive search for Alzheimer disease susceptibility loci in the APOE region

Gyungah Jun, Badri N. Vardarajan, Jacqueline Buros, Chang En Yu, Michele V. Hawk, Beth A. Dombroski, Paul K. Crane, Eric B. Larson, Richard Mayeux, Jonathan L. Haines, Kathryn L. Lunetta, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Lindsay A. Farrer

Hussman Institute for Human Genomics

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-ucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeatlength polymorphism in TOMM40 (poly-T, rs10524523). Design: Conditional logistic regression models and survival analysis. Setting : Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. Main Outcome Measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P < .001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects. Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

Original language	English (US)
Pages (from-to)	1270-1279
Number of pages	10
Journal	Archives of neurology
Volume	69
Issue number	10
DOIs	https://doi.org/10.1001/archneurol.2012.2052
State	Published - Oct 2012

ASJC Scopus subject areas

Arts and Humanities (miscellaneous)
Clinical Neurology

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Jun, G., Vardarajan, B. N., Buros, J., Yu, C. E., Hawk, M. V., Dombroski, B. A., Crane, P. K., Larson, E. B., Mayeux, R., Haines, J. L., Lunetta, K. L., Pericak-Vance, M. A., Schellenberg, G. D., & Farrer, L. A. (2012). Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. Archives of neurology, 69(10), 1270-1279. https://doi.org/10.1001/archneurol.2012.2052

Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. / Jun, Gyungah; Vardarajan, Badri N.; Buros, Jacqueline; Yu, Chang En; Hawk, Michele V.; Dombroski, Beth A.; Crane, Paul K.; Larson, Eric B.; Mayeux, Richard; Haines, Jonathan L.; Lunetta, Kathryn L.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Farrer, Lindsay A.

In: Archives of neurology, Vol. 69, No. 10, 10.2012, p. 1270-1279.

Research output: Contribution to journal › Article › peer-review

Jun, Gyungah ; Vardarajan, Badri N. ; Buros, Jacqueline ; Yu, Chang En ; Hawk, Michele V. ; Dombroski, Beth A. ; Crane, Paul K. ; Larson, Eric B. ; Mayeux, Richard ; Haines, Jonathan L. ; Lunetta, Kathryn L. ; Pericak-Vance, Margaret A. ; Schellenberg, Gerard D. ; Farrer, Lindsay A. / Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. In: Archives of neurology. 2012 ; Vol. 69, No. 10. pp. 1270-1279.

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title = "Comprehensive search for Alzheimer disease susceptibility loci in the APOE region",

abstract = "Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-ucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeatlength polymorphism in TOMM40 (poly-T, rs10524523). Design: Conditional logistic regression models and survival analysis. Setting : Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. Main Outcome Measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P < .001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects. Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.",

author = "Gyungah Jun and Vardarajan, {Badri N.} and Jacqueline Buros and Yu, {Chang En} and Hawk, {Michele V.} and Dombroski, {Beth A.} and Crane, {Paul K.} and Larson, {Eric B.} and Richard Mayeux and Haines, {Jonathan L.} and Lunetta, {Kathryn L.} and Pericak-Vance, {Margaret A.} and Schellenberg, {Gerard D.} and Farrer, {Lindsay A.}",

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AU - Buros, Jacqueline

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AU - Hawk, Michele V.

AU - Dombroski, Beth A.

AU - Crane, Paul K.

AU - Larson, Eric B.

AU - Mayeux, Richard

AU - Haines, Jonathan L.

AU - Lunetta, Kathryn L.

AU - Pericak-Vance, Margaret A.

AU - Schellenberg, Gerard D.

AU - Farrer, Lindsay A.

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N2 - Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-ucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeatlength polymorphism in TOMM40 (poly-T, rs10524523). Design: Conditional logistic regression models and survival analysis. Setting : Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. Main Outcome Measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P < .001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects. Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

AB - Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-ucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeatlength polymorphism in TOMM40 (poly-T, rs10524523). Design: Conditional logistic regression models and survival analysis. Setting : Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. Main Outcome Measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P < .001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects. Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

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