Epistatic genetic effects among Alzheimer's candidate genes

Abstract

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.

Figure 1. PICALM x BIN1 and amyloid deposition.

The top two interactions were rs3851179 at the PICALM locus with rs7561528 (Figure 1A) and with rs744373 (Figure 1B) at the BIN1 locus. Error bars represent standard error. *p < 0.05 (two-tailed).

Figure 2. PICALM x BIN1 Interaction Across Datasets.

The strongest interaction is graphed across the two independent datasets. The top panel displays subjects genotyped on the ADNI-2/GO chip and the bottom panel displays subjects genotyped on the ADNI-1 chip. Error bars represent standard error. *p < 0.05 (two-tailed).