Regeneron’s Population Scale Genomic Study Identifies Several Obesity Controlling Genes

Science has come a long way in understanding nutrition, weight management, and metabolism. However, our understanding of genetic signatures that could help/hinder weight loss remains limited.

Obesity has fast become a pandemic in the last few decades, prompting extensive work on unraveling the interplay of genetic factors, lifestyle choices, and diet in weight loss. With the vast amount of data available from sequencing the human genome, we can now develop a list of genes that may form a network and regulate health and disease.

In an extensive study conducted by the Regeneron Genetics Center, scientists mined genomics data to identify genes and variants that may control body weight.

Discovery of New Body Weight Influencing Genes

In a multi-center study published in Science, the authors sequenced 640,000 exomes from participants in the US, UK, and Mexico. They found 16 genes that had non-synonymous mutations with exome-wide significant Body Mass Index (BMI) association, suggesting these variants play a role in obesity.

Some of these variants, such as those in MC4R and PCSK1, were previously known and validated as obesity markers. Five of the variants were in genes that encode G-protein coupled receptors (GPCRs), specifically those expressed in the hypothalamus, a part of the brain that controls appetite. In addition, they found heterozygous loss-of-function (lof) variants in known obesity genes LEP, POMC, and truncated variants in UBR2 and ANO4. 

The authors validated their findings by analyzing the mechanistic basis of the lof variant of GPR75, a widely observed variant in high frequency and associated with low BMI. The heterozygous variant of GPR75 lowered the odds of obesity by over 50%, while homozygous carriers of GCP75 were more likely to be underweight.

The authors developed heterozygous and homozygous deletion models of GPR75 in mice, and when mice with deletion of GPR75 were put on a high-fat diet, the authors found that GPR75+/- led to 25% and GPR75-/- caused 44% lesser weight gain than wildtype controls and lower levels of body fat, indicating that inactivating GPR75 indeed confers protection against weight gain and accumulation of adipocytes. With further studies, GPR75 can be a therapeutic candidate for weight management. 

Comparing their data on MC4R variants with existing literature, they found that MC4R haploinsufficiency is a predictor for obesity, and there may be a population-level variation in the distribution of MC4R variants, suggesting that large scale studies help in identifying patterns and frequency of effector genes. 

Benefit of GWAS Studies

The study revealed many BMI-associated GPCRs and other rare single-variants with exome-wide association to BMI, indicating that large-scale genome wide association studies (GWAS) are an ideal tool to discover functional variants and effector genes for a wide range of multigenic disorders. Furthermore, this methodology can help our understanding of the complex interplay between rare and common variants in disease development and prevention and identify better drug targets based on genomic insights.

“This is a potentially game-changing discovery that could improve the lives and health of millions of people dealing with obesity, for whom lasting interventions have often been elusive,” Christopher D. Still, D.O., Director for the Geisinger Obesity Research Institute at Geisinger Medical Center, and one of the authors said in a statement.

In an accompanying perspective, Yeo and O’Rahilly from the University of Cambridge Metabolic Research Laboratories (MRL) summarized the importance of the study. “The study of Akbari et al. 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”.

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Author

Sahana Shankar