Genome editing to define the function of risk loci and variants in rheumatic disease

Abstract

Discoveries in human genetic studies have revolutionized our understanding of complex rheumatic and autoimmune diseases, including the identification of hundreds of genetic loci and single nucleotide polymorphisms that potentially predispose individuals to disease. However, in most cases, the exact disease-causing variants and their mechanisms of action remain unresolved. Functional follow-up of these findings is most challenging for genomic variants that are in non-coding genomic regions, where the large majority of common disease-associated variants are located, and/or that probably affect disease progression via cell type-specific gene regulation. To deliver on the therapeutic promise of human genetic studies, defining the mechanisms of action of these alleles is essential. Genome editing technology, such as CRISPR–Cas, has created a vast toolbox for targeted genetic and epigenetic modifications that presents unprecedented opportunities to decipher disease-causing loci, genes and variants in autoimmunity. In this Review, we discuss the past 5–10 years of progress in resolving the mechanisms underlying rheumatic disease-associated alleles, with an emphasis on how genomic editing techniques can enable targeted dissection and mechanistic studies of causal autoimmune risk variants. Genome editing technology, such as CRISPR–Cas, has great potential in the study of rheumatic disease genetics, including in discovering disease-associated genes and regulatory regions, in validating causal variants and in characterizing important cell types and cell states. Hundreds of autoimmune risk loci have been discovered in coding and non-coding regions of the genome; however, their function and the causal alleles functioning within these loci have been difficult to discern. Advances in genomic editing have made it possible to quickly and effectively investigate autoimmune disease-associated loci and variants using a number of approaches in both cell lines and primary cells. CRISPR–Cas genomic editing can be used to induce insertions and deletions, correct precise mutations and induce epigenetic changes to investigate loci and variants associated with rheumatic diseases. CRISPR–Cas screening approaches are effective tools for whole-genome investigation of autoimmune disease-related genes and detailed resolution of autoimmune risk regions. Resolving the heterogeneity of cell types in rheumatic disorders with unbiased single-cell technologies is critical to understanding the genetics of disease. Hundreds of autoimmune risk loci have been discovered in coding and non-coding regions of the genome; however, their function and the causal alleles functioning within these loci have been difficult to discern. Advances in genomic editing have made it possible to quickly and effectively investigate autoimmune disease-associated loci and variants using a number of approaches in both cell lines and primary cells. CRISPR–Cas genomic editing can be used to induce insertions and deletions, correct precise mutations and induce epigenetic changes to investigate loci and variants associated with rheumatic diseases. CRISPR–Cas screening approaches are effective tools for whole-genome investigation of autoimmune disease-related genes and detailed resolution of autoimmune risk regions. Resolving the heterogeneity of cell types in rheumatic disorders with unbiased single-cell technologies is critical to understanding the genetics of disease.