Emerging applications of genome-editing technology to examine functionality of GWAS-associated variants for complex traits

Abstract

Over the last decade, genome-wide association studies (GWAS) have propelled the discovery of thousands of loci associated with complex diseases. The focus is now turning toward the function of these association signals, determining the causal variant(s) among those in strong linkage disequilibrium, and identifying their underlying mechanisms, such as long-range gene regulation. Genome-editing techniques utilizing zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and clustered regularly-interspaced short palindromic repeats with Cas9 nuclease (CRISPR-Cas9) are becoming the tools of choice to establish functionality for these variants, due to the ability to assess effects of single variants in vivo. This review will discuss examples of how these technologies have begun to aid functional analysis of GWAS loci for complex traits such as cardiovascular disease, Type 2 diabetes, cancer, obesity, and autoimmune disease. We focus on analysis of variants occurring within noncoding genomic regions, as these comprise the majority of GWAS variants, providing the greatest challenges to determining functionality, and compare editing strategies that provide different levels of evidence for variant functionality. The review describes molecular insights into some of these potentially causal variants and how these may relate to the pathology of the trait and look toward future directions for these technologies in post-GWAS analysis, such as base-editing.