TY - JOUR
T1 - Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium
AU - Alzheimer's Disease Genetics Consortium
AU - Hohman, Timothy J.
AU - Bush, William S.
AU - Jiang, Lan
AU - Brown-Gentry, Kristin D.
AU - Torstenson, Eric S.
AU - Dudek, Scott M.
AU - Mukherjee, Shubhabrata
AU - Naj, Adam
AU - Kunkle, Brian W.
AU - Ritchie, Marylyn D.
AU - Martin, Eden R.
AU - Schellenberg, Gerard D.
AU - Mayeux, Richard
AU - Farrer, Lindsay A.
AU - Pericak-Vance, Margaret A.
AU - Haines, Jonathan L.
AU - Thornton-Wells, Tricia A.
N1 - Funding Information:
The authors are very grateful to all the individuals and families who have participated in the studies in which these analyses were performed. This project was funded in large part by the following NIH grants: 5R01AG027944 , 1RC2AG036528 , 1P30AG036445 , R01LM010040 , K12HD043483 .
Funding Information:
In addition, the National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC , U01 AG032984 , RC2 AG036528 ; NACC , U01 AG016976 ; NCRAD , U24 AG021886 ; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute P30 AG019610 ; Boston University , P30 AG013846 , U01 AG10483 , R01 CA129769 , R01 MH080295 , R01 AG017173 , R01 AG025259 , R01AG33193 ; Columbia University , P50 AG008702 , R37 AG015473 ; Duke University , P30 AG028377 , AG05128 ; Emory University , AG025688 ; Group Health Research Institute , UO1 AG06781 , UO1 HG004610 ; Indiana University , P30 AG10133 ; Johns Hopkins University , P50 AG005146 , R01 AG020688 ; Massachusetts General Hospital , P50 AG005134 ; Mayo Clinic , P50 AG016574 ; Mount Sinai School of Medicine , P50 AG005138 , P01 AG002219 ; New York University , P30 AG08051 , MO1RR00096 , UL1 RR029893 , 5R01AG012101 , 5R01AG022374 , 5R01AG013616 , 1RC2AG036502 , 1R01AG035137 ; Northwestern University , P30 AG013854 ; Oregon Health & Science University , P30 AG008017 , R01 AG026916 ; Rush University , P30 AG010161 , R01 AG019085 , R01 AG15819 , R01 AG17917 , R01 AG30146 ; TGen , R01 NS059873 ; University of Alabama at Birmingham , P50 AG016582 , UL1RR02777 ; University of Arizona , R01 AG031581 ; University of California, Davis , P30 AG010129 ; University of California, Irvine , P50 AG016573 , P50, P50 AG016575 , P50 AG016576 , P50 AG016577 ; University of California, Los Angeles , P50 AG016570 ; University of California, San Diego , P50 AG005131 ; University of California, San Francisco , P50 AG023501 , P01 AG019724 ; University of Kentucky , P30 AG028383 , AG05144 ; University of Michigan , P50 AG008671 ; University of Pennsylvania , P30 AG010124 ; University of Pittsburgh , P50 AG005133 , AG030653 ; University of Southern California , P50 AG005142 ; University of Texas Southwestern , P30 AG012300 ; University of Miami , R01 AG027944 , AG010491 , AG021547 , AG019757 ; University of Washington , P50 AG005136 ; Vanderbilt University , R01 AG019085 ; and Washington University , P50 AG005681 , P01 AG03991 . The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451, and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGEN series was also funded by NIA grant AG041232, the Banner Alzheimer's Foundation, the Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), the Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, and Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI funding for ADNI is through the Northern California Institute for Research and Education by grants from 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, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering, and NIA grants U01 AG024904, RC2 AG036535, and K01 AG030514. They thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05–14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. The results published here are in part based on data obtained from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Target Discovery Consortium data portal and can be accessed at doi:10.7303/syn2580853. AMP-AD project data were supported by the following NIH grants: P30AG10161, RF1AG15819, R01AG17917, U01AG46152, R01AG36836.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neurobiolaging.2015.10.031
DO - 10.1016/j.neurobiolaging.2015.10.031
M3 - Article
C2 - 26827652
AN - SCOPUS:84962285532
VL - 38
SP - 141
EP - 150
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
ER -