Scientists identify rare gene variants that confer up to 6-fold increase in risk of obesity and more

Good news!

Will we finally be able to tell the difference between factors beyond an individual's control and lifestyle choices causing obesity?

"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 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. ...
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. ...

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.

For this study, the researchers worked ... 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. ..."

From the abstract:

"Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity."

Scientists identify rare gene variants that confer up to 6-fold increase in risk of obesity | University of Cambridge Cambridge researchers have identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease (open access)

Fig. 1: Discovery and replication of new rare variant associations with BMI.