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

Abstract

Background: The 3-dimensional (3D) conformation of the chromatin creates complex networks of noncoding regulatory regions (distal elements) and genes with important implications in gene regulation. Despite the importance of the role of noncoding regions in complex traits, little is known about their interplay within regulatory hubs and the implication in multigenic diseases like schizophrenia. 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.

RetroFun-RVS: a retrospective family-based framework for rare variant analysis incorporating functional annotations

“…This model only considers pairs of gene-enhancer, consistent with previous studies (C. Wu and Pan, 2018). Models extending gene-enhancer pairs to Cis-Regulatory Hubs (CRHs), networks encompassing up to several genes and active enhancers have been proposed (Mangnier et al, 2022). CRHs have been shown to be a relevant model in schizophrenia etiology, explaining more heritability than tissue-and non-tissue-specific elements, and being more effective to link noncoding SNPs to differentially expressed genes in schizophrenia compared to Topologically As-sociated Domains (TADs) or pairs of gene-enhancer.…”

“…This TAD has been selected since it encompasses four CRHs showing different complexities (two genes-five enhancers (CRH1); two genes-two enhancers (CRH2); one gene-one enhancer (CRH3); one gene-four enhancers (CRH4); See Table S1). Refer to Mangnier et al, 2022 for more details. Using RarePedsim (B.…”

“…Also, we assessed the performance in terms of power of our method compared to existing approaches namely, RVS (Bureau et al, 2019) and RV-NPL (Zhao et al, 2019) (Figure S3). Power was evaluated as the proportion of p-values less than α = 8.33e-6, corresponding to the Bonferroni-adjusted 0.05 significance level when testing six thousand independent regions across the genome, corresponding to three thousand TADs (the average number of TADs found in our previous study across cell-types or tissues (Mangnier et al, 2022)), while permitting the same number of additional domains of interest, i.e., outside TADs, to be tested. Results at lower proportion of risk variants and considering small pedigrees were given in the Supplements.…”