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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Alzheimer Disease / genetics*
  • Cadherins / genetics
  • Calcium Channels, L-Type / genetics
  • Datasets as Topic*
  • Disease Progression
  • Epistasis, Genetic / genetics*
  • Female
  • Genetic Association Studies*
  • Humans
  • Male
  • Models, Genetic
  • Phosphatidylethanolamine Binding Protein / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, Adrenergic, alpha-1 / genetics
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Risk
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Saposins / genetics
  • Sirtuin 1 / genetics

Substances

  • ABCB1 protein, human
  • ADRA1A protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • CACNA1C protein, human
  • CDH23 protein, human
  • Cadherins
  • Calcium Channels, L-Type
  • NR2B NMDA receptor
  • PE-binding protein 4, human
  • PSAP protein, human
  • Phosphatidylethanolamine Binding Protein
  • Receptors, Adrenergic, alpha-1
  • Receptors, N-Methyl-D-Aspartate
  • Ryanodine Receptor Calcium Release Channel
  • Saposins
  • SIRT1 protein, human
  • Sirtuin 1

Grant support