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ASHG: Exome-Wide Association Study Reveals Rare Variants Linked to Severe Adult-Onset Obesity

WASHINGTON – Rare protein-truncating variants in the BSN gene are associated with severe adult-onset obesity, according to new data presented by researchers from the University of Cambridge at the American Society of Human Genetics (ASHG) annual meeting here on Wednesday.

The study, which is also available as a MedRxiv preprint, highlights the utility of population-scale exome-wide association studies to detect rare genetic variants underpinning common human diseases.

"As we all know, obesity has become a global epidemic," said Yajie Zhao, a postdoctoral fellow at the Cambridge MRC Epidemiology Unit and the lead author of the study. "So, there is an urgent need for us to know the etiology of obesity."

In general, obesity can be grouped into two categories based on its underlying genetic contributions, he said: monogenic obesity, which is caused by mutations impacting a single gene, and polygenic obesity, which involves a set of genetic variants that each only exert a modest effect on the disease.

Previously, researchers have mostly identified mutations involved in severe, early-onset monogenic obesity, Zhao noted. Meanwhile, genome-wide association studies in large population cohorts have helped identify hundreds of common variants that come with more subtle effects.

"The question is whether we can perform a GWAS-like study to systematically identify mutations with larger effects on BMI using large population cohorts," he said.

According to Zhao, the recent emergence of population-scale whole-exome sequencing data has enabled exome-wide association studies that have led to the discovery of both common and rare variants.

For their study, the Cambridge researchers carried out an exome-wide association analysis for adult body mass index (BMI), leveraging genotyping and phenotyping data from 419,668 individuals of European ancestry from the UK Biobank.

In addition, they replicated their results using independent whole-exome data from 167,359 individuals of non-European ancestry from the Mexico City Prospective Study and the Pakistan Genomic Resource Study.

Through these analyses, the researchers nailed down rare protein-truncating variants (PTVs) — variants that result in a shorter version of a protein — in two genes, BSN and APBA1. These were shown to have "substantially" higher effects on BMI compared to well-established obesity genes such as MC4R, according to the study.

Unlike most other obesity-related genes, PTVs in BSN and APBA1 had no apparent effect on childhood adiposity, Zhao said, indicating they are predominantly implicated in adult-onset obesity.

Furthermore, the researchers found that PTVs in BSN magnified the influence of common BMI-associated genetic variants. A common polygenic score, they reported, had an effect on BMI that was twice as large in individuals with BSN PTVs than in those without.

Beyond that, they also observed that carriers of BSN PTVs had a higher risk of type 2 diabetes and nonalcoholic fatty liver disease.

According to Zhao, BSN encodes Bassoon, a scaffolding protein that is essential for the organization of the presynaptic cytoskeleton and for exocytosis-mediated neurotransmitter release. The researchers hypothesized that the association between BSN PTVs and obesity might be due to aging-related vesicular dysfunction.

To further explore the functional consequences of BSN deletion, Zhao and his collaborators generated CRISPR-Cas9-edited human iPSC-derived hypothalamic neurons with deactivated BSN and performed single-nucleus RNA sequencing to assess transcriptional differences.

These approaches revealed a network of differentially expressed genes, such as NTNG1, that were collectively enriched in genomic regions associated with BMI, the researchers noted, suggesting a role for degenerative neuronal synaptic function and neurotransmitter release in the etiology of obesity.

"Our study further proves that human exome and genome sequencing at scale will become an increasingly important entry point for the discovery of novel mechanistic insight into biology," Zhao said.