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Omnigenic Model

In a small-world network, the number of steps between two random nodes grows at a rate proportional to the logarithm of the number of nodes. Consequently, even in very large small-world networks, nodes are separated by a few steps. The game Six Degrees of Kevin Bacon is a classic illustration.

The Omnigenic Model1 proposes that gene regulatory pathways constitute a small-world network. For a typical trait, even though only a small number of core genes directly control the trait, a large number of peripheral genes are within a few regulatory steps of the core genes. Genetic variants that affect the peripheral genes produce cascading effects through the regulatory network that ultimately affect the core genes and therefore the trait.

A central observation of the modern GWAS era is that the typical complex trait is influenced by a surprisingly large number of variants. The Omnigenic Model explains why: all variants that affect peripheral genes affect the trait.

The following figure, from Boyle et al.1, illustrates the concept:

omnigenic-model

  1. Evan A Boyle, Yang I Li, and Jonathan K Pritchard. An expanded view of complex traits: from polygenic to omnigenic. Cell, 169(7):1177–1186, 2017. URL: https://www.cell.com/cell/fulltext/S0092-8674(17)30629-3. ↩↩