Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Abstract

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein–coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

Loss of Function Glucose-Dependent Insulinotropic Polypeptide Receptor Variants Are Associated With Alterations in BMI, Bone Strength and Cardiovascular Outcomes

“…In addition, we also observed a > 250-fold reduction in the GIP potency in G protein signaling for E288Q compared to wild-type GIPR, and supra-physiological GIP levels were needed for near maximum receptor activation. Similar impairment in terms of cAMP production was also published very recently (Akbari et al, 2021). We, in addition, found that R190Q and E288G displayed a diminished arrestin recruitment that in return resulted in a lack of receptor internalization, consistent with the previously established arrestin dependency for GIPR internalization (Gabe et al, 2018).…”

“…Similarly, we observe an association with BMD, yet no association with risk of fractures. Our observation that carriers of either GIPR variants had lower body fat mass and lean body mass than non-carriers corresponds with a previous association with lower BMI ( Turcot et al, 2018 ), and was confirmed recently by whole-exome sequencing ( Akbari et al, 2021 ). These results suggest that GIPR signaling contributes to regulation of body weight and body composition, and that reduced GIPR signaling is a potentially beneficial strategy against obesity.…”

Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes

“…Exome-sequencing, variant calling, quality control and gene-based tests were performed as previously described 57 . Variant sets tested were pLOF variants ( GIGYF1 and TNRC6B ) or pLOF plus missense variants predicted to be deleterious by 5/5 algorithms ( PFAS ) with MAF < 1%.…”

COVID-19 mitigation by digital contact tracing and contact prevention (app-based social exposure warnings)

“…We also assume all agents have equal transmission probability upon close contact with a susceptible agent. While some meta-analysis studies have found lower secondary attack rates for asymptomatic subjects 17 , a recent study found similar viral load and infectiousness for PAMS (pre-symptomatic, asymptomatic, and mildly-symptomatic) subjects 18 , and no significant differences have been found in some recent contact tracing studies 19 . Also, the same distribution of symptomatic and asymptomatic infections is used in all simulations.…”