Variant-to-function approaches for adipose tissue: Insights into cardiometabolic disorders

Abstract

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic disorders. However, the functional interpretation of these loci remains a daunting challenge. This is particularly true for adipose tissue, a critical organ in systemic metabolism and the pathogenesis of various cardiometabolic diseases. We discuss how variant-to-function (V2F) approaches are used to elucidate the mechanisms by which GWAS loci increase the risk of cardiometabolic disorders by directly influencing adipose tissue. We outline GWAS traits most likely to harbor adipose-related variants and summarize tools to pinpoint the putative causal variants, genes, and cell types for the associated loci. We explain how large-scale perturbation experiments, coupled with imaging and multi-omics, can be used to screen variants’ effects on cellular phenotypes and how these phenotypes can be tied to physiological mechanisms. Lastly, we discuss the challenges and opportunities that lie ahead for V2F research and propose a roadmap for future studies.