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

Author:

Zhao YajieORCID,Chukanova Maria,Kentistou Katherine A.ORCID,Fairhurst-Hunter Zammy,Siegert Anna Maria,Jia Raina Y.,Dowsett Georgina K. C.,Gardner Eugene J.ORCID,Lawler KatherineORCID,Day Felix R.ORCID,Kaisinger Lena R.ORCID,Tung Yi-Chun Loraine,Lam Brian Yee HongORCID,Chen Hsiao-Jou CortinaORCID,Wang Quanli,Berumen-Campos JaimeORCID,Kuri-Morales PabloORCID,Tapia-Conyer RobertoORCID,Alegre-Diaz JesusORCID,Barroso InêsORCID,Emberson JonathanORCID,Torres Jason M.ORCID,Collins Rory,Saleheen Danish,Smith Katherine R.ORCID,Paul Dirk S.ORCID,Merkle FlorianORCID,Farooqi I. Sadaf,Wareham Nick J.ORCID,Petrovski SlavéORCID,O’Rahilly StephenORCID,Ong Ken K.ORCID,Yeo Giles S. H.ORCID,Perry John R. B.ORCID

Abstract

AbstractObesity 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.

Funder

RCUK | Medical Research Council

RCUK | Biotechnology and Biological Sciences Research Council

Wellcome Trust

Chan Zuckerberg Initiative

Publisher

Springer Science and Business Media LLC

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3