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 - 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
SN - 0197-4580
VL - 38
SP - 141
EP - 150
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -