Translating non-coding genetic associations into a better understanding of immune-mediated disease

Abstract

Genome-wide association studies have identified hundreds of genetic loci that are associated with immune-mediated diseases. Most disease-associated variants are non-coding, and a large proportion of these variants lie within enhancers. As a result, there is a pressing need to understand how common genetic variation might affect enhancer function and thereby contribute to immune-mediated (and other) diseases. In this Review, we first describe statistical and experimental methods to identify causal genetic variants that modulate gene expression, including statistical fine-mapping and massively parallel reporter assays. We then discuss approaches to characterise the mechanisms by which these variants modulate immune function, such as clustered regularly interspaced short palindromic repeats (CRISPR)-based screens. We highlight examples of studies that, by elucidating the effects of disease variants within enhancers, have provided important insights into immune function and uncovered key pathways of disease.