Bridging the Gap between Statistical and Biological Epistasis in Alzheimer’s Disease

Abstract

Alzheimer's disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known disease markers. Research has shown that Alzheimer's disease's missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer's disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer's disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer's disease etiology.

Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer’s disease in large cohort

“…Heterogeneity in the genetic causes of AD is certainly present (Mez, 2016), and further erodes power to detect statistical epistasis. Finally, even when statistical evidence for epistasis is detected, it does not necessarily indicate the presence of a physical biological interaction between the implicated proteins (M. T. W. Ebbert et al, 2015). Statistical patterns can be a product of a variety of underlying mechanisms.…”

“…Epistasis occurs when multiple genes interact to create a single phenotype (Cordell, 2002). These kinds of synergetic relationships play a critical role in the etiology of complex diseases, yet remain vastly understudied in AD pathology (“2018 Alzheimer’s disease facts and figures,” 2018; M. T. W. Ebbert, Ridge, & Kauwe, 2015; Raghavan & Tosto, 2017).…”

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk

“…A distinction must be made regarding statistical and biological epistasis, however [22]. While there is evidence that CLU, like CD33, interacts indirectly with MS4A2 [3], little is known about MS4A4E itself and we do not know whether it biologically interacts with CLU.…”

“…In this study, we attempted to replicate these gene-gene interactions using the largest dataset used in an epistasis study, to date [22]. We performed an independent meta-analysis of datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) using 3837 cases and 4145 controls, followed by a combined meta-analysis that included the original Cache County results [3] with an additional 326 cases and 2093 controls.…”

Genetic epistasis regulates amyloid deposition in resilient aging

“…Genetic epistasis may be a major contributor to the “missing heritability” of late-onset Alzheimer’s disease (AD) [1], and recent efforts have demonstrated the importance of evaluating gene-gene interactions among AD risk variants using integrative approaches [2]. Variants within the sortilin-related receptor (SORL1, SORLA, LR11) gene are among the most highly-replicated genetic risk factors for late-onset Alzheimer’s disease (AD); they have been associated with AD diagnosis in candidate studies [3], genome-wide association studies [4], and meta-analyses [5].…”