Hidden Risk Genes with High-Order Intragenic Epistasis in Alzheimer's Disease

Abstract

Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD.

Quantitative proteomic analysis of Parkin substrates in Drosophila neurons

“…Interestingly, both VPS35 and Parkin mutations are also associated with Alzheimer’s Disease (AD) [106–108]. VPS35 interacts with the amyloid precursor protein (APP) sorting receptor, SorL1, which is also an AD causing gene, to regulate APP processing and Aβ production [109–113].…”

“…VPS35 interacts with the amyloid precursor protein (APP) sorting receptor, SorL1, which is also an AD causing gene, to regulate APP processing and Aβ production [109–113]. Parkin has recently been identified as an AD risk gene [108] and decreased Parkin levels have been found in AD patient cerebrospinal fluids [114]. Remarkably, Parkin over-expression has been shown to ameliorate AD symptoms by increasing the clearance of amyloid loads [115, 116], which may suggest that defects in a common endo-lysosomal pathway are shared between PD and AD.…”

Towards a Circuit-Level Understanding of Hippocampal CA1 Dysfunction in Alzheimer's Disease Across Anatomical Axes

“…Superficial and deep cells have different upstream regulators of the JNK kinase pathway (Maroso et al, 2016), which has also been implicated in amyloidogenesis (Ahn et al, 2016). Superficial neurons express higher Nr3c2, the mineralocorticoid receptor, which has been identified as a risk factor in a meta-analysis of AD GWAS (Sun et al, 2014). In the context of higher excitability relating to pathology, intrinsic excitability favors deep neurons but overall synaptic excitability favors superficial neurons.…”

Detecting High-Order Epistasis in Nonlinear Genotype-Phenotype Maps

“…RECENT analyses of genotype-phenotype maps have revealed “high-order” epistasis—that is, interactions between three, four, and even more mutations (Ritchie et al 2001; Segrè et al 2005; Xu et al 2005; Tsai et al 2007; Imielinski and Belta 2008; Matsuura et al 2009; da Silva et al 2010; Pettersson et al 2011; Wang et al 2012; Hu et al 2013; Weinreich et al 2013; Sun et al 2014; Anderson et al 2015; Yokoyama et al 2015). The importance of these interactions for understanding biological systems and their evolution is the subject of current debate (Weinreich et al 2013; Poelwijk et al 2016).…”