Cis-Regulatory Hubs: a new 3D Model of Complex Disease Genetics with an Application to Schizophrenia

The 3-dimensional (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 like 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 schizophrenia-associated genes, schizophrenia-associated SNPs and schizophrenia heritability compared to equivalent structures. Finally, CRHs exhibit larger proportions of genes differentially expressed in schizophrenia compared to 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. Results: Here we show that cis-regulatory hubs (CRHs) in neurons highlight functional interactions between distal elements and promoters, providing a model to explain the epigenetic mechanisms involved in complex diseases. CRHs represent a new 3D model, where several distal elements interact to create a complex network of active genes. Indeed, we found that CRHs represent functional structures, showing higher transcriptional activity. In a disease context, CRHs highlighted strong enrichments in schizophrenia-associated genes, schizophrenia-associated SNPs and schizophrenia heritability compared to equivalent tissue and non-tissue-specific structures. Also, genes, by sharing the same distal elements, converge to common biological processes associated with schizophrenia. Finally, the results showed that in a complex disease etiology, small CRHs by linking fewer distal elements to promoters constitute a more informative structure than larger hubs. Conclusion: CRHs are a new 3D model of the chromatin interactions between gene promoters and their distal elements highlighting causal regulatory processes and providing a better understanding of complex disease etiology such as schizophrenia. Indeed, by providing a finer scale chromosome architecture, we have genetic and statistical evidence that CRHs represent a major advancement in 3D models to study the epigenetic underlying processes involved in complex traits.