Protein-truncating variants inBSNare associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease

Abstract

Obesity is a major risk factor for many common diseases and has a significant heritable component. While clinical and large-scale population studies have identified several genes harbouring rare alleles with large effects on obesity risk, there are likely many unknown genes with highly penetrant effects remaining. To this end, we performed whole 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 on BMI substantially larger than well-established obesity genes such as MC4R. One in ~6500 individuals carry a heterozygous protein truncating variant (PTV) in BSN, which confers a 6.6, 3.7 and 3-fold higher risk of severe obesity (BMI >40kg/m2), non-alcoholic fatty liver disease and type 2 diabetes, respectively. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 had no apparent effect on childhood adiposity. Furthermore, BSN PTVs magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect on BMI twice as large in BSN PTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human iPSC-derived hypothalamic neurons. These approaches highlighted a network of differentially expressed genes that were collectively enriched for genomic regions associated with BMI, and suggest a role for degenerative neuronal synaptic function and neurotransmitter release in the etiology of obesity.

Population scale whole genome sequencing provides novel insights into cardiometabolic health

“…To identify genes associated with either adult BMI or T2D risk, we performed association testing using WGS data available in up to 489,941 UK Biobank participants (see methods). This represents a sample size increase of up to 71,505 individuals compared to our recent WES analyses of the same cohort 9,11 , attributable to both an increase in the number of sequenced samples (N= 35,725) and the inclusion of individuals of non-European ancestry (N= 64,609). Individual geneburden tests were performed by collapsing rare (MAF < 0.1%) variants across 19,457 protein-coding genes.…”

“…Here, we sought to leverage the increased sample size and purported enhanced capture of rare coding variation from UK Biobank WGS data 7 to provide novel insight into the genetic basis of two cardiometabolic traits of major significance to population health; Type 2 Diabetes (T2D) and Body Mass Index (BMI). Previous large-scale WES studies have identified several genes harbouring rare protein coding variants of large effect for these traits [8][9][10][11][12] including examples where heterozygous loss of function either increases (e.g. GIGYF1 for T2D 13 , BSN for obesity 9,14 ) or decreases the risk of disease (e.g.…”

“…Previous large-scale WES studies have identified several genes harbouring rare protein coding variants of large effect for these traits [8][9][10][11][12] including examples where heterozygous loss of function either increases (e.g. GIGYF1 for T2D 13 , BSN for obesity 9,14 ) or decreases the risk of disease (e.g. MAP3K15 for T2D 12 , GPR75 for obesity 8 ).…”

Assessing the genetic contribution of cumulative behavioral factors associated with longitudinal type 2 diabetes risk highlights adiposity and the brain-metabolic axis

“…This is inline with personality-and dietary-related variants being expressed in the brain, 13,[42][43][44][45][46] and recent studies have shown the important effect that brain-related variants have on metabolic health outcomes. 47 The only other tissue type enriched in expression among PXS-T2D-associated genes was the pituitary gland.…”

Clinical phenotypes of adults with monogenic and syndromic genetic obesity

“…Moreover, our lifestyle program allowed the inclusion of patients with CO without a priori suspicion of genetic obesity. Additionally, current obesity gene panels focus on genes causing early‐onset obesity, whereas new literature has suggested that genes such as bassoon presynaptic cytomatrix protein ( BSN ), which is associated with adult‐onset obesity, may play a role as well [28]. Choices had to be made by clinical geneticists with extensive knowledge on genetic obesity regarding which genes to include in the obesity gene panel.…”