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GLP1R (Glucagon-Like Peptide 1 Receptor)

Summary

Glucagon-like peptide 1 receptor (GLP1R) is a G-protein coupled receptor that plays a critical role in glucose homeostasis and appetite regulation. It is the primary biological target for weight-loss and anti-diabetic medications such as semaglutide. A genome-wide association study (GWAS) by the Auton Lab identified a missense variant in the signal peptide of GLP1R (rs10305420, p.Pro7Leu) associated with enhanced weight-loss efficacy and increased risk of side effects.

Biological Role and Disease Association

  • Incretin System: GLP1R is expressed in pancreatic beta cells, where its activation stimulates insulin secretion in a glucose-dependent manner. It is also expressed in the central nervous system (particularly the hypothalamus and hindbrain), where it regulates satiety and delays gastric emptying.
  • Obesity and Diabetes: As a key regulator of energy balance and glycemic control, GLP1R is targeted by GLP-1 Receptor Agonists (such as semaglutide) to treat obesity and type 2 diabetes.

Pharmacogenetics and Genetic Variants

  • rs10305420 (p.Pro7Leu): A missense variant located in the signal peptide region of GLP1R. The T (effect) allele is associated with increased weight-loss efficacy (an additional -0.76 kg of weight loss expected per copy of the effect allele, $P = 2.9 \times 10^{-10}$ as of 2026-04-08). It is hypothesized that the hydrophobic leucine residue increases signal peptide stability, enhancing cell surface trafficking of the receptor. This variant is also associated with an increased likelihood of GLP1 medication-related nausea and vomiting.
  • rs11760106 and rs9357296: Genetic variants in the vicinity of the GLP1R locus associated with vomiting ($P = 2.5 \times 10^{-27}$, OR = 1.57 for the T allele) and nausea ($P = 2.6 \times 10^{-28}$, OR = 1.36 for the G allele), respectively (as of 2026-04-08). These variants co-localize with the Percentage BMI Change GWAS signal, suggesting a shared genetic mechanism where increased efficacy is linked to higher side-effect susceptibility.

Citations