Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study

doi:10.1001/jamaneurol.2014.1491

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study

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

164 Scopus citations

Abstract

IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10^-96), with associations in CR1 (rs6701713, P = 7.2 × 10^-4), BIN1 (rs7561528, P = 4.8 × 10^-4), and PICALM (rs561655, P = 2.2 × 10^-3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7%of the variation in AAO (R² = 0.256) over baseline (R² = 0.221), whereas the other 9 loci together contribute to 2.2%of the variation (R² = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

Original language	English
Pages (from-to)	1394-1404
Number of pages	11
Journal	JAMA Neurology
Volume	71
Issue number	11
DOIs	https://doi.org/10.1001/jamaneurol.2014.1491
State	Published - Nov 1 2014

Bibliographical note

Publisher Copyright:
Copyright 2014 American Medical Association. All rights reserved.

Funding

Funders	Funder number
Eli Lilly and Company
AstraZeneca
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS080820, R01NS059873, P50NS039764
Canadian Institutes of Health Research
Coins for Alzheimer's Research Trust
Stichting MS Research
Higher Education Funding Council for England
National Institute of Biomedical Imaging and Bioengineering
Wellcome Trust
Charles A Dana Foundation
National Institute of Mental Health	P50MH060451, R01MH080295
Newcastle University
Schering Plough Co
UK Medical Research Council, Engineering and Physical Sciences Research Council
Bristol-Myers Squibb
Genentech Incorporated
GE Healthcare
Johnson and Johnson Pharmaceutical Research and Development
GlaxoSmithKline
Howard Hughes Medical Institute
Biomedical Laboratory Research and Development, VA Office of Research and Development
Pfizer
National Childhood Cancer Registry – National Cancer Institute	R01CA129769
National Institute on Aging	P50AG005144, R01AG033193, P50AG005146, RC2AG036535, P50AG005142, R01AG035137, U01AG024904, U24AG021886, R01AG019085, R01AG025259, U01AG016976, P01AG010491, R01AG013616, P50AG005133, RC2AG036528, P50AG005134, R01AG012101, P50AG005131, K01AG030514, P30AG013854, P30AG028383, R01AG027944, P50AG016582, R01AG034504, U01AG010483, P50AG005136, R01AG022374, P50AG025688, R01AG041232, P50AG005138, P50AG023501, R01AG041797, R01AG021547, P50AG005681, P50AG008671, P30AG028377, R01AG041718, R37AG015473, R01AG026916, P01AG019724, R01AG030146, U01AG006781, P50AG016573, P50AG016574, P30AG010133, P30AG013846, R01AG030653, P50AG016570, R01AG017917, P01AG002219, P50AG005128, R01AG015819, U01AG032984, RC2AG036502, R01AG019757, R01AG026390, R01AG020688, R01AG017173, R01AG031581, P30AG008017, U24AG026395, P30AG010124, P30AG012300, P30AG010161, P01AG003991, P30AG019610, P30AG010129, P30AG008051, P50AG008702, RC2 AG036535, AG034504, U01 AG024904, K01 AG030514
Alzheimer's Association	IIRG-05-14147, IIRG-08-89720
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center	R01 AG019085
National Institutes of Health/National Institute of Environmental Health Sciences	P30ES013508
National Center for Advancing Translational Sciences (NCATS)	UL1TR000135, UL1TR001108, UL1TR002529
Northwestern Polytechnical University	P30 AG013854
Miami Clinical and Translational Science Institute, University of Miami	AG027944, AG021547, R01 AG027944, AG010491, AG019757
York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York	UL1 RR029893, P30 AG08051, 5R01AG012101, 1RC2AG036502, MO1RR00096, 5R01AG022374, 1R01AG035137, 5R01AG013616
University of Southern Indiana	P30 AG10133
University of California, Los Angeles	P50 AG016570
Duke-Kunshan University	AG05128, P30 AG028377
Mayo Clinic Rochester	P50 AG016574
Oregon Health and Science University	P30 AG008017, R01 AG026916
Boston University School of Public Health/Boston University Medical Campus	P30 AG013846, U01 AG10483, R01 MH080295, R01 AG017173, R01AG33193, R01 AG025259, R01 CA129769
Univ. of Northern British Columbia	P50 AG008702, R37 AG015473
Massachusetts General Hospital	P50 AG005134
University of Southern California	P50 AG005142
National Center for Research Resources	M01RR000096, UL1RR029893
National Human Genome Research Institute	U01HG004610
University Research Committee, Emory University	AG025688

ASJC Scopus subject areas

Clinical Neurology

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10.1001/jamaneurol.2014.1491

Cite this

@article{02fcee47ad8f4d6cb9f2cfc4d306ed05,

title = "Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study",

abstract = "IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10-96), with associations in CR1 (rs6701713, P = 7.2 × 10-4), BIN1 (rs7561528, P = 4.8 × 10-4), and PICALM (rs561655, P = 2.2 × 10-3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7\%of the variation in AAO (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2\%of the variation (R2 = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.",

author = "Naj, \{Adam C.\} and Gyungah Jun and Christiane Reitz and Kunkle, \{Brian W.\} and William Perry and Park, \{Yo Son\} and Beecham, \{Gary W.\} and Rajbhandary, \{Ruchita A.\} and Hamilton-Nelson, \{Kara L.\} and Wang, \{Li San\} and Kauwe, \{John S.K.\} and Huentelman, \{Matthew J.\} and Myers, \{Amanda J.\} and Bird, \{Thomas D.\} and Boeve, \{Bradley F.\} and Baldwin, \{Clinton T.\} and Jarvik, \{Gail P.\} and Crane, \{Paul K.\} and Ekaterina Rogaeva and Barmada, \{M. Michael\} and Demirci, \{F. Yesim\} and Carlos Cruchaga and Kramer, \{Patricia L.\} and Nilufer Ertekin-Taner and John Hardy and Graff-Radford, \{Neill R.\} and Green, \{Robert C.\} and Larson, \{Eric B.\} and \{St. George-Hyslop\}, \{Peter H.\} and Buxbaum, \{Joseph D.\} and Evans, \{Denis A.\} and Schneider, \{Julie A.\} and Lunetta, \{Kathryn L.\} and Kamboh, \{M. Ilyas\} and Saykin, \{Andrew J.\} and Reiman, \{Eric M.\} and \{De Jager\}, \{Philip L.\} and Bennett, \{David A.\} and Morris, \{John C.\} and Montine, \{Thomas J.\} and Goate, \{Alison M.\} and Deborah Blacker and Tsuang, \{Debby W.\} and Hakon Hakonarson and Kukull, \{Walter A.\} and Foroud, \{Tatiana M.\} and Martin, \{Eden R.\} and Haines, \{Jonathan L.\} and Jicha, \{Gregory A.\} and \{Van Eldik\}, \{Linda J.\}",

year = "2014",

month = nov,

day = "1",

doi = "10.1001/jamaneurol.2014.1491",

language = "English",

volume = "71",

pages = "1394--1404",

number = "11",

}

TY - JOUR

T1 - Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease

T2 - A genome-wide association study

AU - Naj, Adam C.

AU - Jun, Gyungah

AU - Reitz, Christiane

AU - Kunkle, Brian W.

AU - Perry, William

AU - Park, Yo Son

AU - Beecham, Gary W.

AU - Rajbhandary, Ruchita A.

AU - Hamilton-Nelson, Kara L.

AU - Wang, Li San

AU - Kauwe, John S.K.

AU - Huentelman, Matthew J.

AU - Myers, Amanda J.

AU - Bird, Thomas D.

AU - Boeve, Bradley F.

AU - Baldwin, Clinton T.

AU - Jarvik, Gail P.

AU - Crane, Paul K.

AU - Rogaeva, Ekaterina

AU - Barmada, M. Michael

AU - Demirci, F. Yesim

AU - Cruchaga, Carlos

AU - Kramer, Patricia L.

AU - Ertekin-Taner, Nilufer

AU - Hardy, John

AU - Graff-Radford, Neill R.

AU - Green, Robert C.

AU - Larson, Eric B.

AU - St. George-Hyslop, Peter H.

AU - Buxbaum, Joseph D.

AU - Evans, Denis A.

AU - Schneider, Julie A.

AU - Lunetta, Kathryn L.

AU - Kamboh, M. Ilyas

AU - Saykin, Andrew J.

AU - Reiman, Eric M.

AU - De Jager, Philip L.

AU - Bennett, David A.

AU - Morris, John C.

AU - Montine, Thomas J.

AU - Goate, Alison M.

AU - Blacker, Deborah

AU - Tsuang, Debby W.

AU - Hakonarson, Hakon

AU - Kukull, Walter A.

AU - Foroud, Tatiana M.

AU - Martin, Eden R.

AU - Haines, Jonathan L.

AU - Jicha, Gregory A.

AU - Van Eldik, Linda J.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10-96), with associations in CR1 (rs6701713, P = 7.2 × 10-4), BIN1 (rs7561528, P = 4.8 × 10-4), and PICALM (rs561655, P = 2.2 × 10-3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7%of the variation in AAO (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2%of the variation (R2 = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

AB - IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10-96), with associations in CR1 (rs6701713, P = 7.2 × 10-4), BIN1 (rs7561528, P = 4.8 × 10-4), and PICALM (rs561655, P = 2.2 × 10-3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7%of the variation in AAO (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2%of the variation (R2 = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: A genome-wide association study

Abstract

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