A study led by Medical Research Council (MRC) scientists has identified genetic variants in two genes that the investigators say have some of the largest impacts on obesity risk discovered to date.
The researchers, headed by teams at the MRC Epidemiology Unit and the MRC Metabolic Diseases Unit at the Institute of Metabolic Science, both based at the University of Cambridge, used UK Biobank and other data to perform whole exome sequencing of body mass index (BMI) in over 500,000 individuals. The rare protein truncating variants (PTVs) in the genes APBA1 and BSN that the study identified are, the investigators noted, among the first obesity-linked genetic factors identified for which the increased risk of obesity is not observed until adulthood.
The findings indicated that genetic variants in the gene BSN, also known as Bassoon, raised the risk of obesity by 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 potentially affect about 10,000 people in the U.K.
Study author Giles Yeo, PhD, at the MRC Metabolic Diseases Unit, said, “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.”
Yeo and colleagues reported on their study and findings in Nature Genetics, in a paper titled, “Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.” In their paper, they stated, “In conclusion, rare genetic disruptions of APBA1 and BSN have larger impacts on adult BMI and obesity risk than heterozygous disruptions of any previously described obesity risk gene.” The results, they noted, “… collectively suggest emerging roles for neurodevelopment, neurogenesis, and altered neuronal oxidative phosphorylation in the etiology of obesity.”
Obesity is a major public health concern as it is a significant risk factor for other serious diseases, including cardiovascular disease and type 2 diabetes. “Obesity is the second leading cause of preventable death, increasing the risk of diseases such as type 2 diabetes (T2D), cardiovascular disease, and cancer,” the authors wrote. And while obesity has “a substantial heritable component,” they continued, the genetic reasons why some people are more prone to weight gain are incompletely understood.
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. Separately, large-scale population-based genome-wide association studies (GWAS) have separately identified hundreds of common genetic variants associated with body mass index (BMI) in adults, but individually, the effect of each variant is small, the authors noted. “… cumulatively, the ∼ 1,000 common variants identified to date explain only ∼6% of the population variance in BMI.”
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. Yeo et al., exploited whole exome sequencing (WES) data from nearly 420,000 participants of European ancestry from the UK Biobank to carry out an exome-wide association study (ExWAS) for body mass index. The analyses identified the rare loss-of-function variants in the BSN and APBA1 genes. The team then worked closely with AstraZeneca to replicate their findings in additional existing cohorts, using genetic data from more than 165,000 individuals of predominantly non-European ancestry from the Mexico City Prospective Study, and the Pakistan Genomic Resource Study. This is important as the researchers can now apply their findings beyond individuals of European ancestry.
While both BSN and APBA1 encode proteins are 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 from those we already know for previously identified obesity gene variants. “In contrast to almost all previously reported obesity-associated genes, neither BSN nor APBA1 showed any association with childhood body size or puberty timing (P > 0.05), suggesting adult-onset effects on body weight based on the phenotypes available in UK Biobank,” they wrote.
Based on existing 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. Study author John Perry, PhD, 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 authors added, “… we hypothesize that BSN may have widespread involvement in neurodevelopment and neurogenesis, with BSN variants leading to increased appetitive drive. We propose that future studies explore the impact of BSN PTVs on primary appetitive regulatory pathways across the life course.”
If the researchers can better understand the neural biology of obesity, it could present more potential drug targets to treat obesity in the future. Slavé Petrovski, PhD, 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.”
