Cis-regulatory hubs: A new 3D model of complex disease genetics with an application to schizophrenia

Abstract

The 3D conformation of the chromatin creates complex networks of noncoding regulatory regions (distal elements) and promoters impacting gene regulation. Despite the importance of the role of noncoding regions in complex diseases, little is known about their interplay within regulatory hubs and implication in multigenic diseases such as schizophrenia. Here we show that cis-regulatory hubs (CRHs) in neurons highlight functional interactions between distal elements and promoters, providing a model to explain epigenetic mechanisms involved in complex diseases. CRHs represent a new 3D model, where distal elements interact to create a complex network of active genes. In a disease context, CRHs highlighted strong enrichments in schizophreniaassociated genes, schizophrenia-associated SNPs, and schizophrenia heritability compared with equivalent structures. Finally, CRHs exhibit larger proportions of genes differentially expressed in schizophrenia compared with promoter-distal element pairs or TADs. CRHs thus capture causal regulatory processes improving the understanding of complex disease etiology such as schizophrenia. These multiple lines of genetic and statistical evidence support CRHs as 3D models to study dysregulation of gene expression in complex diseases more generally.