期刊
NEUROBIOLOGY OF AGING
卷 38, 期 -, 页码 141-150出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2015.10.031
关键词
Gene-gene interactions; Epistasis; Alzheimer disease; Biofilter
资金
- NIH [5R01AG027944, 1RC2AG036528, 1P30AG036445, R01LM010040, K12HD043483, P30AG10161, RF1AG15819, R01AG17917, U01AG46152, R01AG36836]
- National Institutes of Health, National Institute on Aging (NIH-NIA) [U01 AG032984, RC2 AG036528, U01 AG016976, U24 AG021886, U24 AG026395, U24 AG026390, P30 AG019610, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193, P50 AG008702, R37 AG015473, P30 AG028377, AG05128, AG025688]
- NINDS [NS39764]
- NIMH [MH60451]
- Glaxo Smith Kline
- Kronos Science
- NIA [AG041232, U01 AG024904, RC2 AG036535, K01 AG030514]
- Banner Alzheimer's Foundation
- Johnnie B. Byrd Sr. Alzheimer's Institute
- Medical Research Council
- Newcastle Brain Tissue Resource
- MRC London Brain Bank for Neurodegenerative Diseases
- South West Dementia Brain Bank
- Netherlands Brain Bank
- Institut de Neuropatologia
- Servei Anatomia Patologica
- Universitat de Barcelona
- Abbott
- AstraZeneca AB
- Bayer Schering Pharma AG
- Bristol-Myers Squibb
- Eisai Global Clinical Development
- Elan Corporation
- Genentech
- GE Healthcare
- GlaxoSmithKline
- Innogenetics
- Johnson and Johnson
- Eli Lilly and Co
- Medpace, Inc
- Merck and Co, Inc
- Novartis AG
- Pfizer Inc
- F. Hoffman-La Roche
- Schering-Plough
- Synarc, Inc
- Alzheimer's Association [IIRG-08-89720, IIRG-05-14147]
- Alzheimer's Drug Discovery Foundation
- Dana Foundation
- National Institute of Biomedical Imaging and Bioengineering
- US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program
- [UL1 RR029893]
- [5R01AG012101]
- [5R01AG022374]
- [5R01AG013616]
- [1RC2AG036502]
- [1R01AG035137]
- [P30 AG013854]
- [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]
- [P01 AG002219]
- [P30 AG08051]
- [MO1RR00096]
- [AG010491]
- [AG021547]
- [AG019757]
- [P50 AG005136]
- [P50 AG005681]
- [P01 AG03991]
- [P50 AG005131]
- [P50 AG023501]
- [P01 AG019724]
- [P30 AG028383]
- [AG05144]
- [P50 AG008671]
- [P30 AG010124]
- [P50 AG005133]
- [AG030653]
- [P50 AG005142]
- [P30 AG012300]
- [R01 AG027944]
- [P50 AG016575]
- [P50 AG016576]
- [P50 AG016577]
- [P50 AG016570]
- [UO1 AG06781]
- [UO1 HG004610]
- [P30 AG10133]
- [P50 AG005146]
- [R01 AG020688]
- [P50 AG005134]
- [P50 AG016574]
- [P50 AG005138]
Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate genegene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 x ABCB1, PSAP x PEBP4, and GRIN2B x ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 x CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis. (C) 2016 Elsevier Inc. All rights reserved.
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