Fig. 1

Relationships of general and central adiposity with cardiometabolic diseases and related traits identified through genetic and epigenetic studies. Two common phenotypes have been key to the genetic study of adiposity in humans: body mass index (BMI; in blue), which measures general adiposity; and waist-to-hip ratio adjusted for BMI (WHRadjBMI; in red), which captures central adiposity (that is, fat that collects around the central region of the body and may mark visceral fat deposits). Genome-wide association studies (GWASs) in BMI and WHRadjBMI have revealed 97 and 49 common variant loci, respectively, associated with the traits. While GWASs provide evidence for association between genetic variants and phenotypic outcomes, the variants implicated in these studies can be used in Mendelian randomization (MR) analyses to investigate causal relationships. MR studies using BMI-associated single nucleotide polymorphisms (SNPs) have established causal relationships of BMI on blood pressure, insulin resistance, DNA methylation (that is, alterations in gene expression), diabetes, and coronary heart disease. Similar studies, but for WHRadjBMI-associated SNPs, show similar causal relationships (excluding that for DNA methylation), and a causal role in stroke. The results indicate that not only general adiposity (indexed by BMI) but the distribution of adipose tissue in particular depots (indexed by WHRadjBMI) is crucial to the relationship between adiposity and cardiometabolic disease outcome