| Title: | Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease |
| Journal: | Nature Genetics |
| Published: | 4 Apr 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38575728/ |
| DOI: | https://doi.org/10.1038/s41588-024-01694-x |
| URL: | https://www.nature.com/articles/s41588-024-01694-x.pdf |
Publication 9968
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Abstract
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.</p>
34 Authors
- Yajie Zhao
- Maria Chukanova
- Katherine A. Kentistou
- Zammy Fairhurst-Hunter
- Anna Maria Siegert
- Raina Y. Jia
- Georgina K. C. Dowsett
- Eugene J. Gardner
- Katherine Lawler
- Felix R. Day
- Lena R. Kaisinger
- Yi-Chun Loraine Tung
- Brian Yee Hong Lam
- Hsiao-Jou Cortina Chen
- Quanli Wang
- Jaime Berumen-Campos
- Pablo Kuri-Morales
- Roberto Tapia-Conyer
- Jesus Alegre-Diaz
- Inês Barroso
- Jonathan Emberson
- Jason M. Torres
- Rory Collins
- Danish Saleheen
- Katherine R. Smith
- Dirk S. Paul
- Florian Merkle
- I. Sadaf Farooqi
- Nick J. Wareham
- Slavé Petrovski
- Stephen O'Rahilly
- Ken K. Ong
- Giles S. H. Yeo
- John R. B. Perry
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