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

Alzheimer Disease Genetics Consortium

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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 languageEnglish (US)
Pages (from-to)1394-1404
Number of pages11
JournalJAMA Neurology
Volume71
Issue number11
DOIs
StatePublished - Nov 1 2014

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Genetic Loci
Genome-Wide Association Study
Age of Onset
Alzheimer Disease
Genetic Databases
Onset
Alzheimer's Disease
Genome
Locus

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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

In: JAMA Neurology, Vol. 71, No. 11, 01.11.2014, p. 1394-1404.

Research output: Contribution to journalArticle

Alzheimer Disease Genetics Consortium. / Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease : A genome-wide association study. In: JAMA Neurology. 2014 ; Vol. 71, No. 11. pp. 1394-1404.
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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.",
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TY - JOUR

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

T2 - A genome-wide association study

AU - Alzheimer Disease Genetics Consortium

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 - 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 - Carrasquillo, Minerva M

AU - Dickson, Dennis W

AU - Parisi, Joseph E

AU - Petersen, Ronald Carl

AU - Younkin, Steven G

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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