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.

Keywords: adipocyte; adipogenesis; adipose tissue; body fat distribution; cardiometabolic disease; functional genomics; genome editing; genome-wide association study; non-coding variant; regulatory element.

Graphical abstract

Figure 1

A map of adipocyte biology The figure displays key aspects of adipocyte biology for maintaining adipose tissue function and metabolic health: transcriptional regulation of genes within the nucleus, storage and mobilization of lipids in and out of the adipocytes (lipid turnover), the secretory function of adipocytes, the role of extracellular matrix in the regulation of cell function and behavior, and the interaction of adipocytes with other cell types within adipose tissue.

Figure 2

The variant-to-function framework for adipose tissue biology This figure outlines the main steps in the variant-to-function framework for studying the functional consequences of genetic variants in adipose tissue. These steps include selecting a GWAS locus pertinent for adipose tissue, identifying the causal variant, identifying the effector gene, determining the relevant cell type and state, performing functional experiments to assess the effects on cellular function, and linking these cellular consequences to physiological mechanisms.

Figure 3

Screening natural genetic variation using a GWAS-in-a-dish approach The figure illustrates the GWAS-in-a-dish approach, where adipose tissue-derived stem cells or pre-adipocytes from a genetically heterogeneous population are cultured either in mixed villages (left) or in separate monocultures (right) and then differentiated into adipocytes. By combining donor genotypes with cellular phenotypes, this approach enables GWAS analysis to identify genetic loci associated with various cellular readouts. This facilitates linking natural genetic variation to cellular functions relevant for cardiometabolic disease outcomes.