Investigating Statistical Epistasis in Complex Disorders

Abstract

Abstract. The missing heritability exhibited by late-onset Alzheimer's disease is unexplained and has been partly attributed to epistatic interaction. Methods available to explore this are often based on logistic regression and allow for determination of deviation from an expected outcome as a result of statistical epistasis. Three such methodologies including Synergy Factor and the PLINK modules, -epistasis and -fast-epistasis, were applied to study an epistatic interaction between interleukin-6 and interleukin-10. The models analyzed consisted of two synergistic interactions (SF ≈ 4.2 and 1.6) and two antagonistic interactions (SF ≈ 0.9 and 0.6). As with any statistical test, power to detect association is paramount; and most studies will be underpowered for the task. However, the availability of large sample sizes through genome-wide association studies make it feasible to examine approaches for determining epistatic interactions. This study documents the sample sizes needed to achieve a statistically significant outcome from each of the methods examined and discusses the limitations/advantages of the chosen approaches.

Synergistic interaction between APOE and family history of Alzheimer’s disease on cerebral amyloid deposition and glucose metabolism

“…A positive family history status may represent other susceptibility genes that are either coexpressed or interacting with APOE4. It has been posited that gene-gene interactions account for much of the unexplained variances in AD status [ 31 ] and that these interactions are widespread and common [ 32 ]. For example, clusterin (CLU; involved in AD pathogenesis directly by influencing Aβ aggregation and clearance [ 33 , 34 ]) is found to interact with APOE4 [ 35 , 36 ].…”

Alzheimer’s Disease: Analyzing the Missing Heritability

“…It is also possible that gene-gene interactions account for much of the unexplained variance in AD status [44]. These interactions are widespread and common [45,46] and approaches to understand the effects of epistatic interactions exist and continue to mature [44,47].…”

“…These interactions are widespread and common [45,46] and approaches to understand the effects of epistatic interactions exist and continue to mature [44,47]. Several interesting candidate interactions have been identified and Ebbert et al 2013 (accepted) recently demonstrated that allowing interactions improves the diagnostic utility of the known AD markers.…”

SNCAandmTORPathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

“…The latter, epistasis, is considered the complex effect of one gene upon other genes, and it is also suspected as an important genetic component of complex diseases such as IPD . Still, the potential epistatic effects among different susceptibility risk factors for IPD, despite their plausibility, remain largely neglected and underexplored in this disease …”

“…21 Still, the potential epistatic effects among different susceptibility risk factors for IPD, despite their plausibility, remain largely neglected and underexplored in this disease. 22 In this context, the signaling cascades regulating the neurodegenerative process in PD are not well established, but several pathways have been proposed. 23 Recent studies have reported that deregulation of the mechanistic target of rapamycin (mTOR) pathway occurs in PD.…”