Fat genes which make people up to six times more likely to become obese in adulthood have been discovered by scientists.
Researchers identified genetic variants in two genes that have some of the most significant impacts on the risk of obesity, diabetes and liver disease ever uncovered. And it confirms that some people do have fat genes that make them more likely to pile on the pounds. The study, which involved more than half a million people, could help develop drugs to combat obesity.
The study, led by Medical Research Council (MRC) researchers based at the University of Cambridge, used data from the UK Biobank as well as other sources to perform whole exome sequencing of body mass index (BMI) in over 500,000 people. They found that genetic variants in the genes BSN - also known as Bassoon - and APBA1 can raise the risk of obesity as much as six times.
The genes were also found to be associated with an increased risk of non-alcoholic fatty liver disease and type 2 diabetes. The Bassoon gene variants were found to affect every one in 6,500 adults - equating to around 10,000 people in the UK and 51,000 in the USA.
Obesity is a significant risk factor for serious diseases including cardiovascular disease and type 2 diabetes but the genetic reasons behind why some people are more susceptible to becoming obese are not fully understood. Previous studies have identified several obesity-associated gene variants having large effects from childhood which act through the leptin-melanocortin pathway in the brain and play 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. Also, unlike the previously identified obesity genes, variants in BSN and APBA1 are not associated with childhood obesity.
The researchers therefore believe they may have uncovered a new biological mechanism for obesity that is different from any previously known. The study, published in the journal Nature Genetics, indicates that BSN and APBA1 play a role in the transmission of signals between brain cells, suggesting that age-related neurodegeneration could be affecting appetite control.
Professor John Perry, a study author and MRC Investigator at the University of Cambridge, explained: "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 accessibility of large-scale databases such as UK Biobank has enabled researchers to search for rare gene variants that may be responsible for conditions including obesity. The researchers also worked closely with AstraZeneca to replicate their findings in existing cohorts using genetic data from individuals from Pakistan and Mexico, allowing them to apply their findings beyond individuals solely of European ancestry.
They added that if they 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," said Dr Slave Petrovski, VP of the Centre 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."
Professor Giles Yeo, another author of the study based at the MRC Metabolic Diseases Unit at the University of Cambridge, 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."