Researchers have demonstrated the potential of large-scale whole-exome sequencing in facilitating therapeutic target discovery to combat obesity.
The recent upsurge in obesity and related health complications highlights a need for safe and efficacious therapeutic strategies. Given the heritability of body fatness (adiposity), understanding the genetic contributions to obesity risk and resistance may provide novel insights. Genome-wide association studies (GWAS) have detected thousands of common, small-effect genetic variants associated with body mass index (BMI). BMI is a standard clinical indicator of adiposity. However, establishing the causality of these genes to obesity and translating them into a clinical setting has proven challenging.
Whole-exome sequencing (WES) represents a promising approach towards developing efficacious therapeutics against obesity. By specifically targeting protein-coding regions of the genome, WES detects large-effect coding variants underlying disease phenotypes. Although most variants causing or predisposing individuals to obesity are non-coding, the functional impacts of protein-coding variants are more easily determined and less likely to exert pleiotropic effects. This makes coding variants much more amenable to clinical translation.
The rare causative variants underlying obesity
Recently, researchers led by Regeneron Pharmaceuticals performed WES on more than 640,000 individuals from the UK, the US and Mexico. Their findings, published in Science, revealed rare nonsynonymous variants in 16 genes that were significantly associated with BMI. Most of these genes were highly expressed in the hypothalamus, corroborating previous GWAS observations regarding the role of the central nervous system in energy regulation.
One of these genes was GPR75, a G protein-coupled receptor, which is strongly expressed in the brain. For the first time, rare, loss-of-function variants of GPR75 were found to be associated with lower BMI and obesity risk. Mouse models of diet-induced obesity further demonstrated that a GPR75 knockout protected against weight gain and associated metabolic perturbations in an allele dose-dependent manner. GPR75 inhibition may therefore represent a novel therapeutic strategy for obesity.
Heterozygous loss-of-function variants in two other G protein-coupled receptors, GIPR and GPR151, were also found to associate with lower BMI, supported by analysis of GIPR variants in cell-based expression experiments. Meanwhile, rare deleterious variants in MC4R and PCSK1 were found to be associated with higher BMI and obesity risk. Notably, these genes are involved in the leptin-melanocortin signaling pathway and are previously well-characterised as causative agents of monogenic obesity.
The potential of large-scale exome sequencing in obesity
This study highlights the potential of complementing GWAS and family studies with large-scale WES to better understand the genetic architecture of obesity. While GWAS identifies common, small-effect genes associated with obesity, WES identifies both rare, large-effect causative variants and reveals the direction of causality of such variants, or whether they increase or decrease BMI.
Importantly, this study demonstrates the translational value of WES. Identifying large-effect coding variants provides direction for in vitro and in vivo mechanistic studies that could validate the contributions of specific alleles to obesity risk and protection. WES may finally bridge the gap between the identification of obesity-associated genetic variants and their application in the clinical setting.
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