title: Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium.
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.
authors.affiliation: Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hohman
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Brown-Gentry
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Torstenson
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Naj
authors.affiliation: 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.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Kunkle
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: 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.
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: 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.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: 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.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Vanderbilt Genetics Institute, Department of Molecular Physiology & Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: triciathorntonwells@gmail.com.
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics; D066264:Datasets as Topic; D018450:Disease Progression; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008957:Models, Genetic; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012306:Risk; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D049231:Saposins / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C547713:ADRA1A protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C079146:CACNA1C protein, human; C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D020746:Calcium Channels, L-Type; C121001:NR2B NMDA receptor; C518018:PE-binding protein 4, human; C483345:PSAP protein, human; D049488:Phosphatidylethanolamine Binding Protein; D018340:Receptors, Adrenergic, alpha-1; D016194:Receptors, N-Methyl-D-Aspartate; D019837:Ryanodine Receptor Calcium Release Channel; D049231:Saposins; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Alzheimer disease; Biofilter; Epistasis; Gene-gene interactions
references.citation: Nat Genet. 2011 May;43(5):436-41
references.pmid: 21460841
references.citation: Otol Neurotol. 2014 Feb;35(2):358-65
references.pmid: 24448297
references.citation: Brain Res Mol Brain Res. 2004 Dec 20;132(2):241-59
references.pmid: 15582162
references.citation: PPAR Res. 2008;2008:328172
references.pmid: 18288284
references.citation: Neurobiol Aging. 2004 Sep;25(8):1009-15
references.pmid: 15212825
references.citation: J Neural Transm (Vienna). 2012 Apr;119(4):473-9
references.pmid: 22065208
references.citation: Brain Pathol. 2007 Oct;17(4):347-53
references.pmid: 17610523
references.citation: Bioinformatics. 2009 Dec 15;25(24):3275-81
references.pmid: 19837719
references.citation: BMC Med Genet. 2010;11:162
references.pmid: 21070631
references.citation: J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):278-9
references.pmid: 16421143
references.citation: PLoS One. 2013;8(11):e80839
references.pmid: 24260488
references.citation: J Geriatr Psychiatry Neurol. 2011 Jun;24(2):63-6
references.pmid: 21478475
references.citation: BMC Med Genet. 2007;8 Suppl 1:S3
references.pmid: 17903302
references.citation: Genet Epidemiol. 2011 Jul;35(5):310-7
references.pmid: 21374718
references.citation: Diabetes. 1988 Jun;37(6):780-6
references.pmid: 2838353
references.citation: BioData Min. 2013 Dec 30;6(1):25
references.pmid: 24378202
references.citation: Mol Neurodegener. 2009 Jan 28;4:5
references.pmid: 19173745
references.citation: Arch Gen Psychiatry. 2006 Feb;63(2):168-74
references.pmid: 16461860
references.citation: Neurosci Lett. 2002 Mar 1;320(1-2):77-80
references.pmid: 11849768
references.citation: J Biol Chem. 2006 Aug 4;281(31):21745-54
references.pmid: 16751189
references.citation: Genes Cancer. 2013 Mar;4(3-4):82-90
references.pmid: 24019998
references.citation: Neurobiol Aging. 2012 May;33(5):1003.e1-8
references.pmid: 22015309
references.citation: J Neural Transm (Vienna). 2014 May;121(5):533-42
references.pmid: 24292895
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2642-7
references.pmid: 22308328
references.citation: Nat Genet. 2010 Jul;42(7):608-13
references.pmid: 20526338
references.citation: Neurobiol Aging. 2013 May;34(5):1518.e9-18
references.pmid: 23107432
references.citation: J Alzheimers Dis. 2011;24(4):751-8
references.pmid: 21321396
references.citation: Mol Med Ther. 2012 Dec 13;1(2):106
references.pmid: 23847772
references.citation: Nat Struct Mol Biol. 2009 Aug;16(8):833-9
references.pmid: 19648926
references.citation: J Med Genet. 2004 Apr;41(4):261-5
references.pmid: 15060098
references.citation: Nat Neurosci. 2014 Sep;17(9):1138-40
references.pmid: 25157507
references.citation: J Biol Chem. 2003 Oct 24;278(43):42377-85
references.pmid: 12923177
references.citation: PLoS One. 2012;7(8):e40366
references.pmid: 22899989
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2381-6
references.pmid: 11226248
references.citation: Diabetes. 2007 Dec;56(12):3053-62
references.pmid: 17846126
references.citation: Hum Mol Genet. 2007 Jan 1;16(1):15-23
references.pmid: 17135279
references.citation: J Biol Chem. 1998 Apr 17;273(16):9761-8
references.pmid: 9545313
references.citation: Cell Commun Signal. 2013;11:93
references.pmid: 24330661
references.citation: J Neurosci Res. 2012 Oct;90(10):1970-80
references.pmid: 22715062
references.citation: Int J Mol Epidemiol Genet. 2012;3(1):39-47
references.pmid: 22493750
references.citation: Eur J Pharmacol. 1996 Apr 4;300(1-2):9-16
references.pmid: 8741159
references.citation: Cell. 2010 Jul 23;142(2):320-32
references.pmid: 20655472
references.citation: Arch Neurol. 2007 Sep;64(9):1306-11
references.pmid: 17846270
references.citation: Neuroimage. 2011 Feb 1;54(3):1896-902
references.pmid: 20888920
references.citation: Cell Mol Life Sci. 2006 Mar;63(6):709-22
references.pmid: 16465451
references.citation: Nat Genet. 2013 Dec;45(12):1452-8
references.pmid: 24162737
references.citation: J Alzheimers Dis. 2014;38(1):145-54
references.pmid: 24077433
references.citation: Front Physiol. 2013 Mar 13;4:45
references.pmid: 23494712
references.citation: Neurobiol Aging. 2013 Apr;34(4):1105-15
references.pmid: 23063647
references.citation: Pac Symp Biocomput. 2009;:368-79
references.pmid: 19209715
references.citation: Bioinformatics. 2010 Sep 15;26(18):2336-7
references.pmid: 20634204
references.citation: FASEB J. 2012 Mar;26(3):1204-17
references.pmid: 22173972
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Am J Hum Genet. 2009 Apr;84(4):445-58
references.pmid: 19361613
references.citation: PLoS One. 2010;5(6):e11070
references.pmid: 20552018
references.citation: Hum Genet. 2011 Mar;129(3):273-82
references.pmid: 21132329
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):955-9
references.pmid: 20029940
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14164-9
references.pmid: 20660724
references.citation: PLoS One. 2013;8(11):e79771
references.pmid: 24244562
references.citation: J Hum Genet. 2010 Dec;55(12):796-800
references.pmid: 20844544
references.citation: Mol Psychiatry. 2011 Nov;16(11):1130-8
references.pmid: 21116278
references.citation: Eur J Neurosci. 2006 Oct;24(8):2327-34
references.pmid: 17074053
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Neuron. 2007 Jun 7;54(5):713-20
references.pmid: 17553421
references.citation: Hum Genet. 2014 Jan;133(1):85-93
references.pmid: 24026422
references.citation: BMC Med Genet. 2007;8 Suppl 1:S17
references.pmid: 17903299