ArticleNature genetics2024
Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.
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Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 2 of them syntheses that pooled it.
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34citing papers in PubMed, 2 pooled it
25.3field-weighted citation impact, top 1% of its field
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Who cites it
34 citing papers in PubMed, 2 syntheses or guidelines pooled it, 46 citations in OpenAlex.
- Discovery of obesity genes through cross-ancestry analysis.Nature communications · 2025Pooled it
- Missense variants in FRS3 affect body mass index in populations of diverse ancestries.Nature communications · 2025Pooled it
- Article
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- Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.Nature metabolism · 2026Article
- Genetic variability in the leptin-melanocortin pathway and its role in weight loss.Molecular metabolism · 2026Review
- From identity to function: unveiling the cellular complexity of hypothalamic feeding circuits.Reviews in endocrine & metabolic disorders · 2026Review
- The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration.medRxiv : the preprint server for health sciences · 2026Article
- Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.Acta pharmacologica Sinica · 2026Article
- Integrating common and rare variants improves polygenic risk prediction across diverse populations.Nature communications · 2026Article
- Protein-truncating variants in APBA1 in minors with severe, early-onset obesity: implications for genetic testing.Molecular and cellular pediatrics · 2026Article
- The genetics of obesity: aetiology, prevention and therapy.Nature metabolism · 2026Review
- Interplay between obesity-associated insulin resistance and immune system through the lens of evolutionary medicine.Molecular metabolism · 2026Review
- MiRNAs shape mouse age-independent tissue adaptation to spaceflight via ECM and developmental pathways.Nature communications · 2026Article
- Interactions with polygenic background impact quantitative traits in the UK Biobank.medRxiv : the preprint server for health sciences · 2025Article
- Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Rare Variants in HTRA1, SGTB, and RBM12 Confer Risk of Atherosclerotic Cardiovascular Disease Independent of Traditional Cardiovascular Risk Factors.Circulation. Genomic and precision medicine · 2025Article
- Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution.American journal of human genetics · 2025Article
- Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health.Nature genetics · 2025Article
- Cardiometabolic disease and cardio-oncology: Insights from iPSC models and tissue engineering.Cell reports. Medicine · 2025Review
Corrections and comments
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Authors and funding
34 authors at 7 institutions in 4 countries.
Yajie Zhao *MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0002-2747-0219
Maria Chukanova *Metabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Katherine A Kentistou *MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0002-5816-664X
Zammy Fairhurst-HunterCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Anna Maria SiegertMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Raina Y JiaMRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Georgina K C DowsettMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Eugene J GardnerMRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0001-9671-1533
Katherine LawlerMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0003-4188-1804
Felix R DayMRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0003-3789-7651
Lena R KaisingerMRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0002-0849-3191
Yi-Chun Loraine TungMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Brian Yee Hong LamMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0002-3638-9025
Hsiao-Jou Cortina ChenMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0001-6315-9850
Quanli WangCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Jaime Berumen-CamposExperimental Medicine Research Unit, Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Mexico City, Mexico.ORCID http://orcid.org/0000-0001-6707-3317
Pablo Kuri-MoralesExperimental Medicine Research Unit, Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Mexico City, Mexico.ORCID http://orcid.org/0000-0002-0704-9507
Roberto Tapia-ConyerExperimental Medicine Research Unit, Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Mexico City, Mexico.ORCID http://orcid.org/0000-0003-3814-2904
Jesus Alegre-DiazExperimental Medicine Research Unit, Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Mexico City, Mexico.ORCID http://orcid.org/0000-0001-9390-3871
Inês BarrosoExeter Centre of Excellence for Diabetes Research (EXCEED), University of Exeter Medical School, Exeter, UK.ORCID http://orcid.org/0000-0001-5800-4520
Jonathan EmbersonMRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-7792-9422
Jason M TorresMRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-7537-7035
Rory CollinsClinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Danish SaleheenCenter for Non-Communicable Diseases, Karachi, Pakistan.
Katherine R SmithCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.ORCID http://orcid.org/0000-0002-0329-5938
Dirk S PaulCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.ORCID http://orcid.org/0000-0002-8230-0116
Florian MerkleInstitute of Metabolic Science and Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-8513-2998
I Sadaf FarooqiMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Nick J WarehamMRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0003-1422-2993
Slavé PetrovskiCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.ORCID http://orcid.org/0000-0002-1527-961X
Stephen O'RahillyMetabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0003-2199-4449
Ken K Ong *MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0003-4689-7530
Giles S H Yeo *Metabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.ORCID http://orcid.org/0000-0001-8823-3615
John R B Perry *MRC Epidemiology Unit and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. John.Perry@mrc-epid.cam.ac.uk.ORCID http://orcid.org/0000-0001-6483-3771
University of Cambridge · GBAstraZeneca (United Kingdom) · GBUniversidad Nacional Autónoma de México · MXUniversity of Oxford · GBColumbia University Irving Medical Center · USUniversity of Exeter · GBWellcome/MRC Cambridge Stem Cell Institute · GB
Funding
Discovery of novel therapeutic targets for NASH through deep phenotyping of human knockouts and mechanistic studiesR01DK133694 · NIDDK · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI SALEHEEN, DANISH, TABAS, IRA A · 2022 to 2025
$2.6MMedical Research Council MC_UU_00006/2Medical Research Council MC_UU_00014/5Medical Research Council MC_UU_00017/2Medical Research Council MR/S026193/1Medical Research Council MR/Z504543/1NIDDK NIH HHS R01 DK133694Wellcome Trust
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.
Indexed as
Diabetes Mellitus, Type 2Induced Pluripotent Stem CellsLiver DiseasesNerve Tissue ProteinsAdaptor Proteins, Signal TransducingAdultGenetic Predisposition to DiseaseHumansObesityProteomicsAdaptor Proteins, Signal TransducingAPBA1 protein, humanBSN protein, humanNerve Tissue Proteins
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