Journal
JAMA NEUROLOGY
Volume 71, Issue 11, Pages 1394-1404Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2014.1491
Keywords
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Categories
Funding
- National Institute on Aging [U01 AG032984, RC2 AG036528, U01 AG016976, U24 AG021886, U24 AG026395, R01AG041797, U24 AG026390, P30 AG019610, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193, 1RC2AG036502, 1R01AG035137, P30 AG013854, P50 AG005131, P50 AG023501, P01 AG019724, P30 AG028383, AG05144, R01 AG027944, P01 AG03991, AG05128, AG025688, UO1 AG06781]
- National Institute of Neurological Disorders and Stroke [NS39764]
- National Institute of Mental Health [MH60451]
- GlaxoSmithKline
- Kronos Science
- Alzheimer's Foundation
- Johnnie B. Byrd Sr Alzheimer's Institute
- Medical Research Council
- State of Arizona
- National Health Service trusts
- Newcastle University
- Medical Research Council London Brain Bank for Neurodegenerative Diseases via the Medical Research Council
- South West Dementia Brain Bank
- Higher Education Funding Council for England
- Alzheimer's Research Trust
- BRACE
- North Bristol National Health Service Trust Research and Innovation Department and Dementias and Neurodegeneration)
- Netherlands Brain Bank
- Stichting MS Research
- Brain Net Europe
- Hersenstichting Nederland BreinbrekendWerk
- International Parkinson Fonds
- Internationale Stiching Alzheimer Onderzoek
- Institut de Neuropatologia
- Servei Anatomia Patologica
- Universitat de Barcelona
- Abbott
- AstraZeneca
- Bayer Schering Pharma AG
- Bristol-Myers Squibb
- Eisai Global Clinical Development
- Elan Corporation
- Genentech
- GE Healthcare
- Innogenetics
- Johnson Johnson
- Eli Lilly and Company
- Medpace, Inc
- Merck and Co, Inc
- Novartis AG
- Pfizer
- F. Hoffman-La Roche
- ScheringPlough
- Synarc, Inc
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Dana Foundation
- National Institute of Biomedical Imaging and Bioengineering
- Alzheimer's Association [IIRG-05-14147, IIRG-08-89720]
- Biomedical Laboratory Research Program
- Office of Research and Development
- US Department of Veterans Affairs Administration
- Wellcome Trust
- Howard Hughes Medical Institute
- Canadian Institute of Health Research
- National Institute on Aging. [P30 AG008017, R01 AG026916, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146, R01 NS059873, P50 AG016582, UL1RR02777, R01 AG031581, P30 AG010129, P50 AG016573, P50 AG016575, P50 AG016576, P50 AG016577, P50 AG016570]
- The National Institute on Aging [AG010491, AG027944, AG021547, AG019757, P50 AG008671, P30 AG010124, P50 AG005133, AG030653, AG041718, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG005681, AG034504, U01 AG024904, RC2 AG036535, K01 AG030514, P50 AG008702, R37 AG015473, P30 AG028377]
- The National Institute on Aging. [UO1 HG004610, P30 AG10133, P50 AG005146, R01 AG020688, P50 AG005134, P50 AG016574, P50 AG005138, P01 AG002219, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616]
- Parkinson's UK [G-0907] Funding Source: researchfish
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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 x 10(-96)), with associations in CR1 (rs6701713, P = 7.2 x 10(-4)), BIN1 (rs7561528, P = 4.8 x 10(-4)), and PICALM (rs561655, P = 2.2 x 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 (R-2 = 0.256) over baseline (R-2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R-2 = 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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