Understanding the function of regulatory DNA interactions in the interpretation of non-coding GWAS variants

Abstract

Genome-wide association studies (GWAS) have identified a vast number of variants associated with various complex human diseases and traits. However, most of these GWAS variants reside in non-coding regions producing no proteins, making the interpretation of these variants a daunting challenge. Prior evidence indicates that a subset of non-coding variants detected within or near cis-regulatory elements (e.g., promoters, enhancers, silencers, and insulators) might play a key role in disease etiology by regulating gene expression. Advanced sequencing- and imaging-based technologies, together with powerful computational methods, enabling comprehensive characterization of regulatory DNA interactions, have substantially improved our understanding of the three-dimensional (3D) genome architecture. Recent literature witnesses plenty of examples where using chromosome conformation capture (3C)-based technologies successfully links non-coding variants to their target genes and prioritizes relevant tissues or cell types. These examples illustrate the critical capability of 3D genome organization in annotating non-coding GWAS variants. This review discusses how 3D genome organization information contributes to elucidating the potential roles of non-coding GWAS variants in disease etiology.

Implementing Whole Genome Sequencing (WGS) in Clinical Practice: Advantages, Challenges, and Future Perspectives

“…These genomic loci are particularly important in diagnosing multifactorial genetic diseases. WGS allows for a detailed analysis of non-coding regions, providing the opportunity to identify variants that can affect gene regulation and consequently disease development [ 11 , 12 , 13 ].…”

Loop Catalog: a comprehensive HiChIP database of human and mouse samples

“…In the context of human disease, HiChIP and similar assays provide a 3D view for the annotation of disease associations of non-coding genetic variants identified from GWAS (Fu et al, 2018;Gazal et al, 2022;Giambartolomei et al, 2021;Orozco et al, 2022;Zhong et al, 2022).…”

“…In the context of human disease, HiChIP and similar assays provide a 3D view for the annotation of disease associations of non-coding genetic variants identified from GWAS (Fu et al, 2018; Gazal et al, 2022; Giambartolomei et al, 2021; Orozco et al, 2022; Zhong et al, 2022). Combined with efforts from multiple large consortia for cataloging putative regulatory elements spanning distinct cell types (e.g., ENCODE, BLUEPRINT and Roadmap Epigenomics), mapping such 3D maps of chromatin organization has become a critical piece of the puzzle, which led to formation of the 4D Nucleome Consortium (Dekker et al, 2017; Reiff et al, 2022).…”

SnapHiC-G: identifying long-range enhancer-promoter interactions from single-cell Hi-C data via a global background model

“…Chromatin spatial organization plays an essential role in genome function and gene regulation [1][2][3] . Genome-wide chromatin conformation capture technologies like Hi-C have improved our understanding of the 3D genome structure and aided the discovery of chromatin features at various scales, such as chromosome territories, A/B compartments, topologically associating domains (TADs), and chromatin loops.…”