This month in The Journal

Abstract

The omnigenic hypothesis, which contextualizes the highly polygenic nature of complex traits, proposes that a broad, interconnected gene regulatory network coalesces on a set of core effector genes in relevant tissues. Most heritability, therefore, can be attributed to so-called peripheral pathways comprising the additive trans-effects of many common variants. In this issue, Iakovliev et al. explore a key component of the omnigenic hypothesis by seeking to identify core (or, per the authors’ terminology, sparse effector) genes for type 1 diabetes. The authors propose that core genes can be identified by testing disease association with trans-scores, which represent the aggregation of trans-eQTL and trans-pQTL results. Somewhat reassuringly from a biological standpoint, the putative core genes, which would not be detected through traditional genome-wide association analyses, all function in the immune system. Although the approach put forth by the authors will need to be tested in the context of other complex traits and diseases, it is tempting to begin to speculate how the search for core genes might influence the design and interpretation of future research. As an example, one could envision a shift from fine-mapping approaches aimed at identifying discrete functional variants to those that evaluate trans-scores to identify crucial regulatory networks.