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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Valérie Turcot, Yingchang Lu, Heather M. Highland, Claudia Schurmann, Anne E. Justice, Rebecca S. Fine, Jonathan P. Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E. Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E. Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L. Young, Tamuno Alfred, Mary F. Feitosa, Nicholas G. D. Masca, Alisa K. Manning, Carolina Medina‐Gómez, Poorva Mudgal, Maggie C. Y. Ng, Alex P. Reiner, Sailaja Vedantam, Sara M. Willems, Thomas W. Winkler, Gonçalo R. Abecasis, Katja K.H. Aben, Dewan S Alam, Sameer Alharthi, Matthew Allison, Philippe Amouyel, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Lia E. Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A. Böger, Jette Bork‐Jensen, Michiel L. Bots, Erwin P. Böttinger, Donald W. Bowden, Ivan Brandslund, Gerome Breen, Murray H. Brilliant, Linda Broer, Marco Brumat, Amber Burt, Adam S. Butterworth, Peter T. Campbell, Stefania Cappellani, David J. Carey, Eulalia Catamo, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Yii‐Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, Massimiliano Cocca, Francis S. Collins, James P. Cook, Janie Corley, Jordi Corominas Galbany, Amanda J. Cox, David S. Crosslin, Gabriel Cuéllar-Partida, Angela D’Eustacchio, John Danesh, Gail Davies, Paul I. W. de Bakker, Mark de Groot, Renée de Mutsert, Ian J. Deary, George Dedoussis, Ellen W. Demerath, Martin den Heijer, Anneke I. den Hollander, Hester M. den Ruijter, Joe Dennis, Joshua C. Denny, Emanuele Di Angelantonio, Fotios Drenos, Mengmeng Du, Marie‐Pierre Dubé, Alison M. Dunning, Douglas F. Easton, Todd L. Edwards, David Ellinghaus, Patrick T. Ellinor, Paul Elliott, Εvangelos Εvangelou, Aliki‐Eleni Farmaki, I. Sadaf Farooqi, Jessica D. Faul, Sascha Fauser, Shuang Feng, Ele Ferrannini, Jean Ferrières, José C. Florez, Ian Ford, Myriam Fornage, Oscar H. Franco, André Franke, Paul W. Franks, Nele Friedrich, Ruth Frikke‐Schmidt, Tessel E. Galesloot, Wei Gan, Ilaria Gandin, Paolo Gasparini, Jane Whitney Gibson, Vilmantas Giedraitis, Anette P. Gjesing, Penny Gordon‐Larsen, Mathias Gorski, Hans J. Grabe, Struan F.A. Grant, Niels Grarup, Helen Griffiths, Megan L. Grove, Vilmundur Guðnason, Stefan Gustafsson, Jeff Haessler, Håkon Håkonarson, Anke R. Hammerschlag, Torben Hansen, Kathleen Mullan Harris, Tamara B. Harris, Andrew T. Hattersley, Caroline Hayward, Liang He, Nancy L. Heard‐Costa, Andrew C. Heath, Iris M. Heid, Øyvind Helgeland, Jussi Hernesniemi, Alex W. Hewitt, Oddgeir L. Holmen, G. Kees Hovingh, Joanna M. M. Howson, Yao Hu, Paul L. Huang, Jennifer E. Huffman, M. Arfan Ikram, Erik Ingelsson, Anne Jackson, Jan‐Håkan Jansson, Gail P. Jarvik, Gorm Boje Jensen, Yucheng Jia, Stefan Johansson, Marit E. Jørgensen, Torben Jørgensen, J. Wouter Jukema, Bratati Kahali, René S. Kahn, Mika Kähönen, Pia R. Kamstrup, Stavroula Kanoni, Jaakko Kaprio, Maria Karaleftheri, Sharon L. R. Kardia, Fredrik Karpe, Sekar Kathiresan, Frank Kee, Lambertus A. Kiemeney, Eric H. Kim, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S. Kooner, Charles Kooperberg, Tellervo Korhonen, Péter Kovács, Helena Kuivaniemi, Zoltán Kutalik, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, David Lamparter, Ethan M. Lange, Leslie A. Lange, Claudia Langenberg, Eric B. Larson, Sang Lee, Terho Lehtimäki, Cora E. Lewis, Huaixing Li, Jin Li, Ruifang Li‐Gao, Honghuang Lin, Keng‐Hung Lin, Li‐An Lin, Lin Xu, Lars Lind, Jaana Lindström, Allan Linneberg, Ching‐Ti Liu, Dajiang J. Liu, Ken Sin Lo, Artitaya Lophatananon, Andrew Lotery, Anu Loukola, Jian'an Luan, Steven A. Lubitz, Leo‐Pekka Lyytikäinen, Satu Männistö, Gaëlle Marenne, Angela L. Mazul, Mark I. McCarthy, Roberta McKean‐Cowdin, Sarah E. Medland, Karina Meidtner, Lili Milani, Vanisha Mistry, Paul Mitchell, Karen L. Mohlke, Leena Moilanen, Marie Moitry, Grant W. Montgomery, Dennis O. Mook‐Kanamori, Carmel Moore, Trevor A. Mori, Andrew D. Morris, Andrew P. Morris, Martina Müller‐Nurasyid, Patricia B. Munroe, Mike A. Nalls, Narisu Narisu, Christopher P. Nelson, Matt J. Neville, Sune F. Nielsen, Kjell Nikus, Pål R. Njølstad, Børge G. Nordestgaard, Dale R. Nyholt, Jeffrey R. O’Connel, Michelle L. O’Donoghue, Loes M. Olde Loohuis, Roel A. Ophoff, Katharine R. Owen, Chris J. Packard, Sandosh Padmanabhan, Gerard Pasterkamp, Aniruddh P. Patel, Alison Pattie, Oluf Pedersen, Peggy Peissig, Gina M. Peloso, Craig E. Pennell, Markus Perola, James A. Perry, John R. B. Perry, Tune H. Pers, Thomas N. Person, Annette Peters, Patricia A. Peyser, Ailith Pirie, Ozren Polašek, Tinca J. C. Polderman, Hannu Puolijoki, Olli T. Raitakari, Asif Rasheed, Rainer Rauramaa, Dermot F. Reilly, Frida Renström, Myriam Rheinberger, Paul M. Ridker, John D. Rioux, Manuel A. Rivas, David J. Roberts, Neil R. Robertson, Antonietta Robino, Olov Rolandsson, Igor Rudan, Katherine S. Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Yadav Sapkota, Naveed Sattar, Robert E. Schoen, Pamela J. Schreiner, Matthias B. Schulze, Robert A. Scott, Marcelo P. Segura-Lepe, Svati H. Shah, Wayne H-H Sheu, Xueling Sim, Andrew J. Slater, Kerrin S. Small, Albert V. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K. Speliotes, John M. Starr, Kāri Stefánsson, Valgerður Steinthórsdóttir, Kathleen Stirrups, Konstantin Strauch, Heather M. Stringham, Michael Stümvoll, Liang Sun, Praveen Surendran, Amy J. Swift, Hayato Tada, Katherine E. Tansey, Jean‐Claude Tardif, Kent D. Taylor, Alexander Teumer, Deborah J. Thompson, Guðmar Þorleifsson, Unnur Þorsteinsdóttir, Betina H. Thuesen, Anke Tönjes, Gerard Tromp, Stella Trompet, Emmanouil Tsafantakis, Jaakko Tuomilehto, Anne Tybjærg‐Hansen, Jonathan P. Tyrer, Rudolf Uher, André G. Uitterlinden, Matti Uusitupa, Sander W. van der Laan, Cornelia M. van Duijn, Nienke van Leeuwen, Jessica van Setten, Mauno Vanhala, Anette Varbo, Tibor V. Varga, Rohit Varma, Digna R. Velez Edwards, Sita H. Vermeulen, Giovanni Veronesi, Henrik Vestergaard, Véronique Vitart, Thomas Vogt, Uwe Völker, Dragana Vuckovic, Lynne E. Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A. Wang, Shuai Wang, Yiqin Wang, Erin B. Ware, Nicholas J. Wareham, Helen R. Warren, Dawn Waterworth, Jennifer Wessel, Harvey D. White, Cristen J. Willer, James G. Wilson, Daniel R. Witte, Andrew R. Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Pang Yao, Laura M. Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Wei Zhao, Wei Zhou, Krina T. Zondervan, Jerome I. Rotter, J. Andrew Pospisilik, Fernando Rivadeneira, Ingrid B. Borecki, Panos Deloukas, Timothy M. Frayling, Guillaume Lettre, Kari E. North, Cecilia M. Lindgren, Joel N. Hirschhorn, Ruth J. F. Loos
Bibliographic record
VenueNature Genetics · 2017
Typearticle
Languageen
FieldMedicine
TopicDiet and metabolism studies
Canadian institutionsYork UniversityUniversité de MontréalDalhousie UniversityMontreal Heart Institute
FundersFP7 Ideas: European Research CouncilCarolina Population Center, University of North Carolina at Chapel HillNational Institute of Child Health and Human DevelopmentNational Institute of Environmental Health SciencesNational Institute of Neurological Disorders and StrokeNational Center for Research ResourcesNational Institute of General Medical SciencesNational Human Genome Research InstituteNational Institute on Drug AbuseNational Institute on AgingNational Institute of Diabetes and Digestive and Kidney DiseasesNorwegian Institute of Public HealthDanish Agency for Science and Higher EducationNational Health and Medical Research CouncilNational Heart, Lung, and Blood InstituteBiotechnology and Biological Sciences Research CouncilCanadian Institutes of Health ResearchForsknings- og InnovationsstyrelsenDirectorate for Biological SciencesNational Institutes of HealthDiabetesforeningenMRC-PHE Centre for Environment and HealthCentre for Cognitive Ageing and Cognitive EpidemiologyH. Lundbeck A/SHjartaverndInstitut de Cardiologie de MontréalFondation Institut de Cardiologie de MontréalMedical Research CouncilServierRegione LombardiaBoehringer Ingelheim StiftungNational Center for Advancing Translational SciencesEconomic and Social Research CouncilUniversità degli Studi di VeronaFondation LeenaardsA.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene FormaalSydäntutkimussäätiöUniversitetet i BergenAarhus Universitets ForskningsfondMax-Planck-GesellschaftDeutsche ForschungsgemeinschaftNederlandse Organisatie voor Wetenschappelijk OnderzoekMinistero della SaluteRegion HovedstadenEuropean Hematology AssociationNovo NordiskBritish Heart FoundationBundesministerium für Bildung und ForschungStrategiske ForskningsrådZonMwSystemsX.chSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungEuropean Foundation for the Study of DiabetesCancer Research UKNational University of SingaporeImperial College Healthcare NHS TrustWellcome TrustAarhus UniversitetAustralian GovernmentNorges ForskningsrådQIMR Berghofer Medical Research InstituteAstraZenecaNational Institute for Health Research Health Protection Research UnitEuropean CommissionSteno Diabetes Center CopenhagenNorges Teknisk-Naturvitenskapelige UniversitetWake Forest School of MedicineHelse VestJohns Hopkins UniversitySundhed og Sygdom, Det Frie ForskningsrådNational Cancer InstituteLundbeckfondenFoundation for Cardiovascular ResearchQueen Mary University of LondonNational Institute for Health and Care ResearchNational Science FoundationMassachusetts General HospitalIstituto Superiore di SanitàImperial College LondonEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentGlaxoSmithKlineErasmus Medisch CentrumAndrea and Charles Bronfman PhilanthropiesNovo Nordisk FondenAmerican Heart AssociationDiabetesforbundetPfizer
KeywordsBiologyBody mass indexObesityEnergy expenditureGeneticsEnergy metabolismEndocrinologyInternal medicine
Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.002
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.010
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.014
GPT teacher head0.250
Teacher spread0.236 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations428
Published2017
Admission routes2
Has abstractyes