Exploring the omnigenic architecture of selected complex traits

Genome-wide association studies (GWASs) have statistically identified thousands of loci influencing a trait of interest. To explain the organizational principles among the functionally often unrelated encoded proteins, the omnigenic model postulates core genes with direct and peripheral genes with indirect effects on molecular trait etiology. However, both core genes and the network paths by which they are influenced are unknown for most traits. Using our previously developed Speos framework to identify core genes, we here focus on the autoimmune disease ulcerative colitis (UC) to explore the regulatory relationships between core and peripheral genes and their organization in multi-modal molecular networks. The identified core genes are characterized by tissue-specific expression and trait-relevant network connections. Using genome-scale perturbation data, we demonstrate that one-third of overexpression or knockdown perturbations impact core genes differently than peripheral genes, a pattern that is not observed for GWAS or random genes. This coordinated perturbation response by core genes was robust across traits and cell lines, despite differing causal perturbagens, suggesting a universal core-gene property. Intriguingly, co-perturbation simulations suggest frequent genetic interactions between core genes, highlighting the role of non-additive interactions previously not considered in the omnigenic model. Thus, physiologically relevant core-gene sets occupy a central position in the underlying molecular network, resulting in genome-wide coordinated regulation. As previous theoretical studies have shown that coordinated regulation of core genes could explain much of the missing heritability, our qualitative observation can provide a foundation for detailed quantitative analyses.