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

Alzheimer's Disease Genetics Consortium

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)141-150
Number of pages10
JournalNeurobiology of Aging
Volume38
DOIs
StatePublished - 2016

Fingerprint

Genetic Association Studies
Alzheimer Disease
Genes
Single Nucleotide Polymorphism
Multifactorial Inheritance
Endophenotypes
Genome-Wide Association Study
Epigenomics
Datasets
Gene Expression

Keywords

  • Alzheimer disease
  • Biofilter
  • Epistasis
  • Gene-gene interactions

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

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

In: Neurobiology of Aging, Vol. 38, 2016, p. 141-150.

Research output: Contribution to journalArticle

@article{6c6aff542a2d408cadaf2f130c061e35,
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.",
keywords = "Alzheimer disease, Biofilter, Epistasis, Gene-gene interactions",
author = "{Alzheimer's Disease Genetics Consortium} and Hohman, {Timothy J.} and Bush, {William S.} and Lan Jiang and Brown-Gentry, {Kristin D.} and Torstenson, {Eric S.} and Dudek, {Scott M.} and Shubhabrata Mukherjee and Adam Naj and Kunkle, {Brian W.} and Ritchie, {Marylyn D.} and Martin, {Eden R} and Schellenberg, {Gerard D.} and Richard Mayeux and Farrer, {Lindsay A.} and Pericak-Vance, {Margaret A} and Haines, {Jonathan L.} and Thornton-Wells, {Tricia A.}",
year = "2016",
doi = "10.1016/j.neurobiolaging.2015.10.031",
language = "English (US)",
volume = "38",
pages = "141--150",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",

}

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.

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.

KW - Alzheimer disease

KW - Biofilter

KW - Epistasis

KW - Gene-gene interactions

UR - http://www.scopus.com/inward/record.url?scp=84962285532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962285532&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2015.10.031

DO - 10.1016/j.neurobiolaging.2015.10.031

M3 - Article

VL - 38

SP - 141

EP - 150

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -