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Title | Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Hohman TJ, Bush WS, Jiang L, Brown-Gentry KD, Torstenson ES, Dudek SM, Mukherjee S, Naj A, Kunkle BW, Ritchie MD, Martin ER, Schellenberg GD, Mayeux R, Farrer LA, Pericak-Vance MA, Haines JL, Thornton-Wells TA |
Corporate Authors | Alzheimer's Disease Genetics Consortium |
Journal | Neurobiol Aging |
Volume | 38 |
Pagination | 141-150 |
Date Published | 2016 Feb |
ISSN | 1558-1497 |
Keywords | Alzheimer Disease, ATP Binding Cassette Transporter, Subfamily B, Cadherins, Calcium Channels, L-Type, Datasets as Topic, Disease Progression, Epistasis, Genetic, Female, Genetic Association Studies, Humans, Male, Models, Genetic, Phosphatidylethanolamine Binding Protein, Polymorphism, Single Nucleotide, Receptors, Adrenergic, alpha-1, Receptors, N-Methyl-D-Aspartate, Risk, Ryanodine Receptor Calcium Release Channel, Saposins, Sirtuin 1 |
Abstract | 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 gene-gene 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 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × 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. |
DOI | 10.1016/j.neurobiolaging.2015.10.031 |
Alternate Journal | Neurobiol. Aging |
PubMed ID | 26827652 |
PubMed Central ID | PMC4735733 |
Grant List | P30 AG013854 / AG / NIA NIH HHS / United States P50 MH060451 / MH / NIMH NIH HHS / United States K01 AG030514 / AG / NIA NIH HHS / United States MH60451 / MH / NIMH NIH HHS / United States UL1 TR001445 / TR / NCATS NIH HHS / United States R01 AG022374 / AG / NIA NIH HHS / United States U01 AG046152 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States R01 AG17917 / AG / NIA NIH HHS / United States M01 RR000096 / RR / NCRR NIH HHS / United States RC2 AG036528 / AG / NIA NIH HHS / United States AG041232 / AG / NIA NIH HHS / United States P30 AG028377 / AG / NIA NIH HHS / United States RF1 AG015819 / AG / NIA NIH HHS / United States P50 AG008671 / AG / NIA NIH HHS / United States R01AG36836 / AG / NIA NIH HHS / United States P50 AG005142 / AG / NIA NIH HHS / United States U01 AG10483 / AG / NIA NIH HHS / United States P30 AG10133 / AG / NIA NIH HHS / United States R01 AG035137 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States P50 AG005128 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States R01 AG031581 / AG / NIA NIH HHS / United States P50 AG016574 / AG / NIA NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States P50 AG016577 / AG / NIA NIH HHS / United States 1P30AG036445 / AG / NIA NIH HHS / United States R01 AG019085 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG013616 / AG / NIA NIH HHS / United States R01 AG030146 / AG / NIA NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States 5R01AG027944 / AG / NIA NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States UL1 RR029893 / RR / NCRR NIH HHS / United States P50 AG016575 / AG / NIA NIH HHS / United States T32 MH065215 / MH / NIMH NIH HHS / United States / / Medical Research Council / United Kingdom AG05128 / AG / NIA NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States P50 NS039764 / NS / NINDS NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P30 AG008051 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States RC2 AG036502 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States R01AG17917 / AG / NIA NIH HHS / United States 1R01AG035137 / AG / NIA NIH HHS / United States R01 MH080295 / MH / NIMH NIH HHS / United States P01 AG03991 / AG / NIA NIH HHS / United States R01 AG026390 / AG / NIA NIH HHS / United States RC2 AG036535 / AG / NIA NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States AG010491 / AG / NIA NIH HHS / United States P30 AG08051 / AG / NIA NIH HHS / United States P30 AG012300 / AG / NIA NIH HHS / United States NS39764 / NS / NINDS NIH HHS / United States R01 AG012101 / AG / NIA NIH HHS / United States P50 AG016573 / AG / NIA NIH HHS / United States 5R01AG022374 / AG / NIA NIH HHS / United States P30 AG036445 / AG / NIA NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States P50 AG016570 / AG / NIA NIH HHS / United States U01AG46152 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States R01AG33193 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R01 AG15819 / AG / NIA NIH HHS / United States U24 AG026390 / AG / NIA NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States 1RC2AG036502 / AG / NIA NIH HHS / United States M01RR00096 / RR / NCRR NIH HHS / United States AG030653 / AG / NIA NIH HHS / United States AG025688 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States R37 AG015473 / AG / NIA NIH HHS / United States U24 AG026395 / AG / NIA NIH HHS / United States AG05144 / AG / NIA NIH HHS / United States R01 CA129769 / CA / NCI NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States U01 AG010483 / AG / NIA NIH HHS / United States P01 AG002219 / AG / NIA NIH HHS / United States U01 AG006781 / AG / NIA NIH HHS / United States U01 AG06781 / AG / NIA NIH HHS / United States P50 AG005144 / AG / NIA NIH HHS / United States P01 AG010491 / AG / NIA NIH HHS / United States R01 AG021547 / AG / NIA NIH HHS / United States R01 AG041232 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States R01 AG019757 / AG / NIA NIH HHS / United States R01 AG020688 / AG / NIA NIH HHS / United States K12 HD043483 / HD / NICHD NIH HHS / United States L30 AG048601 / AG / NIA NIH HHS / United States 5R01AG012101 / AG / NIA NIH HHS / United States R01 AG030653 / AG / NIA NIH HHS / United States K12HD043483 / HD / NICHD NIH HHS / United States R01 AG027944 / AG / NIA NIH HHS / United States R01 AG30146 / AG / NIA NIH HHS / United States R01 AG017173 / AG / NIA NIH HHS / United States R01 AG025259 / AG / NIA NIH HHS / United States P30AG10161 / AG / NIA NIH HHS / United States R01 LM010040 / LM / NLM NIH HHS / United States U01 HG004610 / HG / NHGRI NIH HHS / United States RF1AG15819 / AG / NIA NIH HHS / United States R01LM010040 / LM / NLM NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States P50 AG016582 / AG / NIA NIH HHS / United States 5R01AG013616 / AG / NIA NIH HHS / United States P50 AG016576 / AG / NIA NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States AG019757 / AG / NIA NIH HHS / United States R01 AG026916 / AG / NIA NIH HHS / United States R01 NS059873 / NS / NINDS NIH HHS / United States AG021547 / AG / NIA NIH HHS / United States UL1RR02777 / RR / NCRR NIH HHS / United States R01 AG036836 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States 1RC2AG036528 / AG / NIA NIH HHS / United States |