Genetic Variants Found to Significantly Impact Obesity Risk

A study spearheaded by researchers from the Medical Research Council (MRC) has pinpointed genetic variations within two genes, which stand out for their substantial influence on obesity risk, marking a significant breakthrough in this field.

The unearthing of rare mutations within the BSN and APBA1 genes represents a pioneering discovery in the realm of obesity-related genetics, particularly notable for the absence of heightened obesity susceptibility until adulthood.

Published in Nature Genetics, the study was conducted by scholars affiliated with the MRC Epidemiology Unit and the MRC Metabolic Diseases Unit, housed within the Institute of Metabolic Science at the esteemed University of Cambridge.

Leveraging data from the UK Biobank and other sources, the researchers undertook comprehensive exome sequencing encompassing over 500,000 individuals to delve into the genetic underpinnings of body mass index (BMI).

Their investigation revealed that variants within the BSN gene, alternatively known as Bassoon, could elevate the risk of obesity by up to sixfold, concurrently correlating with an augmented likelihood of non-alcoholic fatty liver disease and type 2 diabetes.

Notably, these Bassoon gene variations were discerned to impact approximately 1 in 6,500 adults, potentially affecting around 10,000 individuals across the UK.

Delving into the neurological aspect of obesity, it is imperative to recognize its profound implications as a pivotal determinant of various debilitating conditions such as cardiovascular disease and type 2 diabetes. Nonetheless, the precise genetic mechanisms underlying susceptibility to weight gain remain inadequately elucidated.

While antecedent investigations have spotlighted numerous genetic variants associated with obesity, predominantly exerting their influence from childhood through the leptin-melanocortin pathway in the brain, the involvement of BSN and APBA1 genes in this pathway remains uncertain. Moreover, unlike previously identified obesity-related genes, mutations within BSN and APBA1 are not linked to childhood obesity.

This intriguing revelation has spurred researchers to speculate that they may have stumbled upon a novel biological framework governing obesity, distinct from established pathways implicated in known obesity gene variants.

Drawing from a synthesis of published research and laboratory experiments detailed in their paper, which underscore the roles of BSN and APBA1 in intercellular signaling within the brain, the researchers propose that age-related neurodegeneration could perturb appetite regulation.

“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.” – Professor John Perry, study author and MRC Investigator at the University of Cambridge

The utilization of global datasets The availability of extensive databases like the UK Biobank has empowered scholars to explore rare genetic variants potentially implicated in various conditions, including obesity. In this investigation, the researchers collaborated closely with AstraZeneca to validate their discoveries across existing cohorts utilizing genetic information from individuals hailing from Pakistan and Mexico. This endeavor holds significance as it broadens the applicability of the researchers’ findings beyond individuals of European descent.

Should the researchers achieve a deeper comprehension of the neural biology underlying obesity, it could unveil a plethora of prospective targets for pharmaceutical intervention in combating obesity in the future.

Dr. Slavé Petrovski, Vice President of the Centre for Genomics Research at AstraZeneca, remarked:

“Rigorous large-scale studies such as this are expediting the pace at which we unearth novel insights into the biology of human diseases. Through collaborative efforts spanning academia and industry, harnessing global datasets for validation, and embracing a genomic-centric approach to healthcare on a broader scale, we are poised to enhance our understanding of diseases – ultimately benefiting patients.”

Future avenues for exploration Professor Giles Yeo, a contributing author to the study affiliated with the MRC Metabolic Diseases Unit, elaborated:

“We have identified two genes housing variants that exert the most profound impact on obesity risk at a population level to date. More significantly, we have discerned that variations in Bassoon are associated with adult-onset rather than childhood obesity. Consequently, these findings afford us fresh insights into the intricate interplay between genetics, neurodevelopment, and obesity.”

For more information: Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease. Nature Genetic, https://doi.org/10.1038/s41588-024-01694-x