Genetic variants in two genes have some of the largest impacts on obesity risk discovered to date. The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood. The findings were reported by researchers at the MRC and the Medical Research Council’s (MRC) Epidemiology Unit and its Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.
"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,” explained Professor John Perry, study author and an MRC Investigator at the University of Cambridge. “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."
Previous research has identified several obesity-associated gene variants conferring large effects from childhood, acting through the leptin-melanocortin pathway in the brain, which plays a key role in appetite regulation.
However, while both BSN and APBA1 encode proteins found in the brain, they are not currently known to be involved in the leptin-melanocortin pathway. In addition, unlike the obesity genes previously identified, variants in BSN and APBA1 are not associated with childhood obesity. This has led the researchers to believe that they may have uncovered a new biological mechanism for obesity, different to those we already know for previously identified obesity gene variants.
The researchers used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals. They found that genetic variants in the gene BSN, also known as Bassoon, can raise the risk of obesity as much as six times and was also associated with an increased risk of non-alcoholic fatty liver disease and of type 2 diabetes. The Bassoon gene variants were found to affect 1 in 6,500 adults, so could affect about 10,000 people in the UK.
"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,” said Professor Giles Yeo, study author based at the MRC Metabolic Diseases Unit. “Thus these findings give us a new appreciation of the relationship between genetics, neurodevelopment and obesity."
Based on published research and laboratory studies, which indicate that BSN and APBA1 play a role in the transmission of signals between brain cells, the researchers suggest that age-related neurodegeneration could be affecting appetite control.
For this study, the researchers worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico. This is important as the researchers can now apply their findings beyond individuals of European ancestry. If the researchers can better understand the neural biology of obesity, it could present more potential drug targets to treat obesity in the future.
"Rigorous large-scale studies such as this are accelerating the pace at which we uncover new insights into human disease biology,” added Dr Slavé Petrovski, VP of the Center for Genomics Research at AstraZeneca. “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."
The study, ‘Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease’, was published in Nature Genetics. To access this paper, please click here
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