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

Obesity 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 – BSN and APBA1 – with effects on BMI substantially larger than well-established obesity genes such as MC4R . One in ∼6500 individuals carry a heterozygous protein truncating variant (PTV) in BSN , which confers a 6.6, 3.7 and 3-fold higher risk of severe obesity (BMI >40kg/m[2][1]), non-alcoholic fatty liver disease and type 2 diabetes, respectively. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 had no apparent effect on childhood adiposity. Furthermore, BSN PTVs magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect on BMI twice as large in BSN PTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion 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. ### Competing Interest Statement Z. F.-H., Q.W., K.R.S, D.S.P., and S.P. are current employees and/or stockholders of AstraZeneca. J.R.B.P and E.G are employees and shareholders of Adrestia Therapeutics. ### Funding Statement 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, British Heart Foundation, and the UK Medical Research Council (MC\_UU\_00017/2). These funding sources had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication. We thank the participants and investigators in the UKB study who made this work possible (Resource Application Number 26041; 9905) the UKB 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 analysis of sequencing and phenotype data. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (REC reference 13/NW/0157, ) as a Research Tissue Bank (RTB) approval and informed consent () was provided by each participant. The MCPS study was approved by the Mexican Ministry of Health, the Mexican National Council for Science and Technology, and the University of Oxford.The institutional review board at the Center for Non-Communicable Diseases (IRB: 00007048, IORG0005843, FWAS00014490) approved the Pakistan Genomic Resource study and all participants gave informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The UK Biobank phenotype and whole-exome sequencing data described here are publicly available to registered researchers through the UKB data access protocol. Information about registration for access to the data is available at: . Data for this study were obtained under Resource Application Numbers 26041 and 9905. The Mexico City Prospective Study welcomes open access and collaboration data requests from bona fide researchers. For more details on accessibility, the study's Data and Sample Sharing policy may be downloaded (in English or Spanish) from . Available study data can be examined in detail through the study's Data Showcase, available at . [1]: #ref-2