Trans Effects on Gene Expression Can Drive Omnigenic Inheritance

Highlights

• We propose a quantitative phenotype model based on core and peripheral genes

• Model is parameterized using data on cis and trans heritability of gene expression

• Analysis implies that heritability explained by trans-acting variants is at least 70%

• Co-regulation of core genes can further amplify the contribution of trans effects

Summary

Early genome-wide association studies (GWASs) led to the surprising discovery that, for typical complex traits, most of the heritability is due to huge numbers of common variants with tiny effect sizes. Previously, we argued that new models are needed to understand these patterns. Here, we provide a formal model in which genetic contributions to complex traits are partitioned into direct effects from core genes and indirect effects from peripheral genes acting in trans. We propose that most heritability is driven by weak trans-eQTL SNPs, whose effects are mediated through peripheral genes to impact the expression of core genes. In particular, if the core genes for a trait tend to be co-regulated, then the effects of peripheral variation can be amplified such that nearly all of the genetic variance is driven by weak trans effects. Thus, our model proposes a framework for understanding key features of the architecture of complex traits.