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

Abstract

AbstractObesity 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 –BSNandAPBA1– with effects on BMI substantially larger than well-established obesity genes such asMC4R. One in ∼6500 individuals carry a heterozygous protein truncating variant (PTV) inBSN, 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 inBSNandAPBA1had no apparent effect on childhood adiposity. Furthermore,BSNPTVs magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect on BMI twice as large inBSNPTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures ofBSNPTV carriers as well as the functional consequences ofBSNdeletion 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.