New Genetic Variants Significantly Increase Risk of Adult Obesity

Researchers from the Medical Research Council (MRC) have discovered rare genetic variants in two genes, BSN and APBA1, that can dramatically increase the risk of obesity in adulthood. The study, published in Nature Genetics, is one of the first to identify obesity-related genes where the increased risk is not observed until adulthood.

The researchers used data from the UK Biobank and other sources to analyze the genetic information of over 500,000 individuals. They found that variants in the BSN gene, also known as Bassoon, can raise the risk of obesity by up to six times and are also associated with an increased risk of non-alcoholic fatty liver disease and type 2 diabetes. These variants are estimated to affect about 10,000 people in the UK.

Obesity is a significant public health concern, as it increases the risk of serious diseases like cardiovascular disease and type 2 diabetes. While previous research has identified several gene variants that contribute to childhood obesity, the genetic reasons why some adults are more prone to weight gain are less understood.

The researchers believe that the variants in BSN and APBA1 may represent a new biological mechanism for obesity, different from those associated with previously identified obesity gene variants. Unlike the genes linked to childhood obesity, which are involved in the brain’s leptin-melanocortin pathway that regulates appetite, BSN and APBA1 are not currently known to be part of this pathway.

Professor John Perry, study author and an MRC Investigator at the University of Cambridge, said: “These findings represent another example of the power of large-scale human population genetic studies to enhance our understanding of the biological basis of disease. The genetic variants we identify in BSN confer some of the largest effects on obesity, type 2 diabetes and fatty liver disease observed to date and highlight a new biological mechanism regulating appetite control.”

The researchers suggest that age-related neurodegeneration could be affecting appetite control, based on published research and laboratory studies indicating that BSN and APBA1 play a role in the transmission of signals between brain cells.

To ensure their findings apply beyond individuals of European ancestry, the researchers collaborated with AstraZeneca to replicate their results using genetic data from individuals from Pakistan and Mexico. This global approach is crucial for understanding the broader implications of these genetic variants.

Dr Slavé Petrovski, VP of the Centre for Genomics Research at AstraZeneca, said: “Rigorous large-scale studies such as this are accelerating the pace at which we uncover new insights into human disease biology. By collaborating across academia and industry, leveraging global datasets for validation, and embedding a genomic approach to medicine more widely, we will continue to improve our understanding of disease – for the benefit of patients.”

A better understanding of the neural biology of obesity could lead to more potential drug targets for treating obesity in the future. Professor Giles Yeo, study author based at the MRC Metabolic Diseases Unit, added: “We have identified two genes with variants that have the most profound impact on obesity risk at a population level we’ve ever seen, but perhaps more importantly, that the variation in Bassoon is linked to adult-onset and not childhood obesity. Thus these findings give us a new appreciation of the relationship between genetics, neurodevelopment and obesity.”

This groundbreaking research highlights the importance of large-scale genetic studies and global collaboration in uncovering new insights into complex diseases like obesity. As researchers continue to explore the genetic basis of obesity, their findings may lead to the development of more targeted and effective treatments for this growing public health concern.

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