Common Genomic Variation Alone Cannot Account for Complex Traits

2166 WordsFeb 25, 20189 Pages
Since the first genome-wide association study (GWAS) in 2005, it has become increasingly evident that common genomic variation alone cannot account for complex traits (3). While GWAS’ have helped understand certain traits and diseases, most studies have linked sequence-variation to only 1.1-1.5 fold increase in risk (3-5). Pursuit of the "missing heritability" has taken the form of both utilization of next-generation sequencing to uncover rare variation and more recently, studies of epigenetic regulation (4, 6). Epigenetics stems from the observation that genotypically identical cells can exhibit alternative and stably heritable phenotypes. These traits, along with the chromosomal mechanisms that produce them and ensure their propagation without alterations in the primary DNA sequence, are referred to as “epigenetic.”(7-9). Alternatively, regions in the genome where the epigenetic state varies and results in alternative phenotypes are referred to as “epialleles” (10). Epigenetic variation adds a regulatory layer to genome function (11). This environment-dependent regulation is implicated in many fundamental biological processes including developmental cell differentiation (9), stem cell function, aging (12) and disease progression and relapse (11, 13-15). Furthermore, understanding epigenetics paves the way for pharmaceutically targeting maladaptive variation (13, 16, 17). At a molecular level, epigenetics variation manifests itself in the way DNA is packaged in the

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