Journal Article

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

Berumen-Campos, Jaime, Chukanova, Maria, Lawler, Katherine, Day, Felix R., Petrovski, Slavé, Jia, Raina Y., Merkle, Florian, Ong, Ken K., Emberson, Jonathan, Barroso, Inês, Yeo, Giles S. H., Dowsett, Georgina K. C., Siegert, Anna Maria, Alegre-Diaz, Jesus, Wareham, Nick J., Kentistou, Katherine A., Torres, Jason M., Paul, Dirk S., Farooqi, I. Sadaf, Perry, John R. B., Smith, Katherine R., Gardner, Eugene J., Fairhurst-Hunter, Zammy, Zhao, Yajie, O’Rahilly, Stephen, Chen, Hsiao-Jou Cortina, Saleheen, Danish, Kuri-Morales, Pablo, Kaisinger, Lena R., Wang, Quanli, Tapia-Conyer, Roberto, Tung, Yi-Chun Loraine, Collins, Rory, Lam, Brian Yee Hong

2024

Overview

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. Analyses of whole-exome sequencing data identify rare loss-of-function variants in BSN associated with adult-onset obesity, type 2 diabetes and fatty liver disease, with stronger effect sizes than those observed for variants in known obesity risk genes such as MC4R.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 692/308/2056 / 692/699/2743/393 / Adaptor Proteins, Signal Transducing - genetics / Adipose tissue / Adult / Agriculture / Animal Genetics and Genomics / Bassoon protein / Biobanks / Biomedical and Life Sciences / Biomedicine / Body mass index / Body size / Cancer Research / Children / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - genetics / Fatty liver / Gene Function / Genes / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Human Genetics / Humans / Hypothalamus / Induced Pluripotent Stem Cells / Liver Diseases / Mutation / Nerve Tissue Proteins - genetics / Obesity / Obesity - complications / Obesity - genetics / Pluripotency / Proteins / Proteomics / Risk factors / Stem cells