NEW YORK – By digging into genetic sequence and phenotypic data for nearly 590,000 adults from the UK, Mexico, and Pakistan, a team led by investigators at the University of Cambridge School of Clinical Medicine and AstraZeneca's Centre for Genomics Research has focused in on rare loss-of-function variants linked to high body mass index (BMI) and obesity in adulthood.
"This study has identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date," John Perry, a researcher affiliated with the University of Cambridge MRC Epidemiology Unit and corresponding author of a paper appearing in Nature Genetics on Thursday, said in an email.
By analyzing exome sequence profiles for 419,668 UK Biobank participants with available BMI measurements, the researchers identified rare loss-of-function variants that coincided with extreme weight gain — which they termed "severe adult-onset obesity" — in adults.
The team highlighted rare variants in two genes in particular: the BSN gene, which codes for a protein called Bassoon that has a role in presynaptic cytoskeletons in neurons, and the APBA1 gene, which codes for a neuronal adaptor protein that interacts with the amyloid precursor protein.
Ties between rare BSN and APBA1 variants and significantly increased BMI were subsequently validated in other populations groups, using exome sequence and BMI data for nearly 167,400 more individuals enrolled in the Pakistan Genomic Resource study and the Mexico City Prospective Study.
The team found that rare BSN variants that boost obesity risk by up to sixfold appeared to contribute to increased risk of type 2 diabetes and non-alcoholic fatty liver disease, Perry explained, noting that rare, adult BMI-related genetic variants in the Bassoon-coding gene are estimated to affect roughly 1 in every 6,500 adults in the UK.
Intriguingly, the investigators' follow-up analyses suggested that protein-truncating variants in the gene appeared to boost the effects of common genetic variants previously linked to BMI, as well as the impact of common variant-based BMI polygenic risk scores.
Based on findings from subsequent gene expression analyses and CRISPR-Cas9-based gene editing experiments in hypothalamic neurons derived from induced pluripotent stem cells, the investigators suggested that BSN and APBA1 may contribute to brain cell signaling processes.
Despite the genes' apparent activity in the brain, the investigators noted that they appear to act via a mechanism that is distinct from the brain's leptin-melanocortin pathway, which has been linked to body weight regulation going back to childhood.
Moreover, the newly detected BSN and APBA1 variants did not seem to influence childhood weight gain, Perry explained, suggesting they likely influence adult BMI and related features through a distinct pathway.
"The genes identified here fall outside of well-established biological pathways that influence risk of these diseases," he said. "Uncovering new biology is the first step towards identifying and developing novel therapeutic targets, so we hope future studies build on these early observations."