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Neurobiol Aging. 2016 Feb;38:141-150. doi: 10.1016/j.neurobiolaging.2015.10.031. Epub 2015 Nov 6.

Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium.

Author information

1
Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
3
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
4
Department of Medicine, University of Washington, Seattle, WA, USA.
5
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
6
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
7
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
8
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA.
9
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
10
Gertrude H. Sergievsky Center, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
11
Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA; Department of Neurology, Boston University, Boston, MA, USA; Department of Ophthalmology, Boston University, Boston, MA, USA; Department of Epidemiology, Boston University, Boston, MA, USA; Department of Biostatistics, Boston University, Boston, MA, USA.
12
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
13
Vanderbilt Genetics Institute, Department of Molecular Physiology & Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: triciathorntonwells@gmail.com.

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.

KEYWORDS:

Alzheimer disease; Biofilter; Epistasis; Gene-gene interactions

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