Scientists at deCODE genetics, a subsidiary of Amgen, and collaborators have published a study in Nature Communications reporting a rare missense variant in FRS3 that associates with decreased body mass index (BMI) and protection against obesity. This missense variant was discovered in a meta-analysis of genome-wide association studies that included 2 million individuals of diverse ancestries.
According to the World Health Organization, in 2022, 2.5 billion adults worldwide (43%) were overweight, and of those, 890 million (16% of all adults) were obese. Obesity is a major risk factor for many diseases, including type 2 diabetes and various cardiovascular disorders. Therefore, it is a global health crisis that requires an expanded range of treatment options for effective management.
In the article, the scientists describe a rare missense variant in FRS3 that is only found among individuals from Finland. This variant is associated with a 1.1 kg/m2 decrease in BMI, equivalent to a 3.5 kg weight loss for a person of average height. Furthermore, carriers are 34% less likely to develop obesity than non-carriers. This missense variant results in a substitution of one amino acid in the FRS3 protein, which likely leads to an increase in its activity. FRS3 takes part in the BDNF-TrkB signaling pathway, an important pathway in regulating energy balance within the brain’s hypothalamus. Increased activity of this signaling pathway leads to reduced appetite and food intake, which is a key feature of obesity treatment.