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

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Peer-reviewed

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Authors

Chukanova, Maria 
Kentistou, Katherine A  ORCID logo  https://orcid.org/0000-0002-5816-664X
Fairhurst-Hunter, Zammy 
Siegert, Anna Maria 

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.

Description

Acknowledgements: We thank the participants and investigators in the UK Biobank study who made this work possible (resource application number 26041; 9905), the UK Biobank Exome Sequencing Consortium (UKB-ESC) members AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen, Bristol-Myers Squibb, Pfizer, Regeneron and Takeda for funding the generation of the data; the Regeneron Genetics Center for completing the sequencing and initial quality control of the exome sequencing data; and the AstraZeneca Centre for Genomics Research analytics and informatics team for processing and analyzing the sequencing and phenotype data. We thank the physicians who referred people to the GOOS and the participants and families for their involvement. Y.Z., K.A.K., R.Y.J., E.J.G., F.R.D., L.R.K., N.J.W., K.K.O. and J.R.B.P. are supported by the UK MRC (Unit Programmes MC_UU_00006/1 and MC_UU_00006/2). M.C. and A.M.S. are supported by a project grant from the MRC (MR/S026193/1). Y.-C.L.T., B.Y.H.L. and G.S.H.Y. are supported by the MRC Metabolic Diseases Unit (MC_UU_00014/1). G.K.C.D. is supported by the BBSRC Doctoral Training Programme. The MCPS has received funding from the Mexican Health Ministry, the National Council of Science and Technology for Mexico, the Wellcome Trust (058299/Z/99), Cancer Research UK, the British Heart Foundation and the UK MRC (MC_UU_00017/2). I.S.F. is supported by a Wellcome Principal Research Fellowship (207462/Z/17/Z), the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and an NIHR Senior Investigator award. I.B. acknowledges funding from an ‘Expanding Excellence in England’ award from Research England. F.M. is a New York Stem Cell Foundation−Robertson Investigator (NYSCF-R-156) and is supported by the Wellcome Trust and Royal Society (211221/Z/18/Z) and a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative (CZI NDCN 191942). This work was supported by the NIHR Exeter Biomedical Research Centre. Next-generation sequencing was performed at the Institute of Metabolic Science Genomics and Bioinformatics Core supported by the MRC (MC_UU_00014/5) and the Wellcome Trust (208363/Z/17/Z) and the Cancer Research UK Cambridge Institute Genomics Core. This study was supported by the NIHR Cambridge Biomedical Research Centre. These funding sources had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication.


Funder: Chan Zuckerberg Initiative (CZI NDCN 191942)

Keywords

Adult, Humans, Adaptor Proteins, Signal Transducing, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Induced Pluripotent Stem Cells, Liver Diseases, Nerve Tissue Proteins, Obesity, Proteomics

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

56

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (207462/Z/17/Z)
Wellcome Trust (208363/Z/17/Z)
Wellcome Trust (211221/Z/18/Z)
MRC (MR/S026193/1)
MRC (MC_UU_00006/1)
MRC (MC_UU_00006/2)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/5)