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Rare Variants in G Protein-Coupled Receptor Gene May Provide Protection From Obesity

NEW YORK – Rare variants within a G protein-coupled receptor gene expressed in the brain may protect people from becoming obese, a new exome sequencing-based analysis suggests. The gene, the Regeneron Pharmaceuticals-led team added, could be harnessed as a treatment strategy for obesity.

Previous studies have uncovered mutations in more than 20 genes that have a large influence on body-mass index as well as hundreds of common variants that have smaller effects on BMI. In a new exome-sequencing analysis of a multiethnic cohort of more than 640,000 individuals, the researchers identified more than a dozen genes associated with BMI. Of these, five were brain-expressed GPCRs, and protein-truncating variants in one of those, GPR75, were linked to 54 percent lower odds of developing obesity, as the researchers reported in Science. Functional analyses in mice further confirmed that loss of GPR75 in mice led to resistance to weight gain.

"GPR75 is a G-protein coupled receptor, one of the largest classes of drug targets, which raises the [idea] that it may be successfully modulated therapeutically," senior author Luca Lotta, the executive director and head of cardiovascular, metabolic, and skeletal human genetics at the Regeneron Genetics Center, said in an email.

The researchers sequenced the whole exomes of 645,626 individuals, including individuals of European ancestry from the UK Biobank and Geisinger's MyCode Community Health Initiative cohorts and individuals of admixed American ancestry from the Mexico City Prospective Study. In a meta-analysis of the three cohorts, they identified 16 genes in which rare nonsynonymous genetic variants were associated with BMI. An exome-sequencing-based approach, Lotta noted, can typically make it easier to tie variants to particular genes, uncover the directionality of association for protein-truncating variants, and follow up on in in vitro and in animal models.

These genes included two in which rare mutations are known to cause monogenic obesity, MC4R and PCSK1, and two others, GPR151 and GIPR, in which rare coding variants have previously been tied to obesity.

Five of the 16 genes encoded GPCRs that are expressed in the brain or central nervous system, particularly in the hypothalamus, which is involved in regulating energy balance. The researchers focused on alterations in the GPR75 gene, which had a large effect size, was associated with lower BMI, and was found in about 4 of every 10,000 people sequenced. They additionally estimated that heterozygous carriers of a loss-of-function variant in GPR75 had 54 percent lower odds of obesity, as compared to non-carriers.

Further, in a mouse model of obesity, mice lacking GPR75 gained less weight on a high-fat diet in a dose-dependent manner. Mice on the diet typically double their weight after 14 weeks, but mice lacking one copy of GPR75 gained about 25 percent less weight than their wild-type counterparts, and mice lacking both versions of GPR75 gained 44 percent less weight. Additionally, mice without GPR75 were also resistant to high fat diet-induced impairments in glucose tolerance and insulin sensitivity, indicating that GPR75 is involved in regulating energy balance.

This suggested to the researchers that inhibiting GPR75 could be a potential treatment strategy for obesity. According to Regeneron, researchers there are already investigating multiple approaches — using antibodies, small molecules, and gene silencing — to target GPR75 therapeutically.

In a related commentary, also appearing in Science, Giles Yeo from the University of Cambridge Metabolic Research Laboratories and Stephen O'Rahilly from Addenbrooke's Hospital noted that the study underscores how exome sequencing can be used to gain insight into mechanisms of mammalian biology. "The study … clearly demonstrates that when sufficient rare human alleles of functional impact can be detected, and when relevant associated phenotypic information is available, then new, robust, and potentially translatable biological insights can be delivered with high efficiency," they added.

Lotta added that his team is, in addition to teasing out the mechanism underlying the effect they uncovered at GPR75, also interested in applying this approach to other diseases to uncover genetic variants that naturally protect people from disease. "These 'golden nuggets' hidden in the human genome can help shed light on pathways which may be modified therapeutically to prevent or treat disease," he said.

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