Epistatic genetic effects among Alzheimer's candidate genes

PLoS One. 2013 Nov 18;8(11):e80839. doi: 10.1371/journal.pone.0080839. eCollection 2013.


Background: Novel risk variants for late-onset Alzheimer's disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition.

Methods: We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with (18)F-AV-45.

Results: Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele.

Conclusions: Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Amyloidogenic Proteins / metabolism
  • Apolipoproteins E / genetics
  • Databases, Genetic
  • Epigenesis, Genetic*
  • Epistasis, Genetic
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Monomeric Clathrin Assembly Proteins / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Tumor Suppressor Proteins / genetics


  • Adaptor Proteins, Signal Transducing
  • Amyloidogenic Proteins
  • Apolipoproteins E
  • BIN1 protein, human
  • Genetic Markers
  • Monomeric Clathrin Assembly Proteins
  • Nuclear Proteins
  • PICALM protein, human
  • Tumor Suppressor Proteins