Genetic variants have been discovered that can raise the risk of obesity by as much as six times.
The rare variants are among the first for which the increased risk of obesity is not seen until adulthood.
They were found in the genes BSN and APBA1 and their impact is among the biggest on obesity risk identified so far.
The study, published in Nature Genetics, led by the MRC Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge.
They used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in more than 500,000 individuals.
They found variants in the gene BSN, also known as Bassoon, raised the risk of obesity by as much as six times and were 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, meaning they could impact about 10,000 people in the UK.
Prof 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 genetic reasons for obesity are not fully understood but earlier research has found several obesity-associated gene variants that lead to large effects from childhood. These act through the leptin-melanocortin pathway in the brain, which plays a key role in appetite regulation.
Both BSN and APBA1 encode proteins found in the brain, but are not known to be involved in this pathway and, unlike the obesity genes previously identified, variants in BSN and APBA1 are not associated with childhood obesity.
The research indicates BSN and APBA1 play a role in the transmission of signals between brain cells, prompting the scientists to suggest that age-related neurodegeneration could be affecting appetite control.
Obesity is a significant risk factor for serious diseases including cardiovascular disease and type 2 diabetes.
If the researchers can understand the neural biology of obesity, it could lead to potential drug targets.
They worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico, meaning the findings can be applied beyond individuals of European ancestry.
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.”
Prof 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.”
