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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
Anne E. Justice, Thomas W. Winkler, Mary F. Feitosa, Misa Graff, Virginia Fisher, Kristin L. Young, Llilda Barata, Xuan Deng, Jacek Czajkowski, David Hadley, Julius S. Ngwa, Tarunveer S. Ahluwalia, Audrey Y. Chu, Nancy L. Heard‐Costa, Elise Lim, Jeremiah Perez, John D. Eicher, Zoltán Kutalik, Luting Xue, Anubha Mahajan, Frida Renström, Joseph Wu, Qibin Qi, Shafqat Ahmad, Alfred Tamuno, Najaf Amin, Lawrence F. Bielak, Amélie Bonnefond, Jennifer Bragg, Gemma Cadby, Martina Chittani, Scott Coggeshall, Tanguy Corre, Neşe Direk, Joel Eriksson, Krista Fischer, Mathias Gorski, Marie Neergaard Harder, Momoko Horikoshi, Tao Huang, Jennifer E. Huffman, Anne Jackson, Johanne Marie Justesen, Stavroula Kanoni, Leena Kinnunen, Marcus E. Kleber, Pirjo Komulainen, Meena Kumari, Unhee Lim, Jian’an Luan, Leo‐Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Jonathan Marten, Rita P. S. Middelberg, Martina Müller‐Nurasyid, Pau Navarro, Louis Përusse, Natalia Pervjakova, Cinzia Sarti, Albert V. Smith, Jennifer A. Smith, Alena Stančáková, Rona J. Strawbridge, Heather M. Stringham, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W. van der Laan, Peter J. van der Most, Jana V. van Vliet‐Ostaptchouk, Sailaja Vedantam, Niek Verweij, Jacqueline M. Vink, Véronique Vitart, Ying Wu, Loïc Yengo, Weihua Zhang, Wei Zhao, Martina E. Zimmermann, Niha Zubair, Gonçalo R. Abecasis, Linda S. Adair, Saima Afaq, Uzma Afzal, Stephan J. L. Bakker, Traci M. Bartz, John Beilby, Richard N. Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin P. Böttinger, Daniele Braga, Brendan M. Buckley, Steven Buyske, Harry Campbell, John C. Chambers, Francis S. Collins, Joanne E. Curran, Gert J. de Borst, Anton J. M. de Craen, Eco J. C. de Geus, George Dedoussis, Graciela E. Delgado, Hester M. den Ruijter, Guðný Eiríksdóttir, Anna L. Eriksson, Tõnu Esko, Jessica D. Faul, Ian Ford, Terrence Forrester, Karl Gertow, Bruna Gigante, Nicola Glorioso, Jian Gong, Harald Grallert, Tanja B. Grammer, Niels Grarup, Saskia Haitjema, Göran Hallmans, Anders Hamsten, Torben Hansen, Tamara B. Harris, Catharina A. Hartman, Maija Hassinen, Nicholas D. Hastie, Andrew C. Heath, Dena Hernández, Lucia A. Hindorff, Lynne J. Hocking, Mette Hollensted, Oddgeir L. Holmen, Georg Homuth, Jie Huang, Joseph Hung, Nina Hutri‐Kähönen, Erik Ingelsson, John-Olov Jansson, Marjo‐Riitta Järvelin, Min A. Jhun, Marit E. Jørgensen, Markus Juonala, Mika Kähönen, Magnus K. Karlsson, Heikki A. Koistinen, Ivana Kolčić, Genovefa Kolovou, Charles Kooperberg, Bernhard K. Krämer, Johanna Kuusisto, Kirsti Kvaløy, Timo A. Lakka, Claudia Langenberg, Lenore J. Launer, Karin Leander, Sang Lee, Lars Lind, Cecilia M. Lindgren, Allan Linneberg, Stéphane Lobbens, Marie Loh, Mattias Lorentzon, Robert Luben, Gitta H. Lubke, Anja Ludolph-Donislawski, Sara Lupoli, Pamela A. F. Madden, Reija Männikkö, Pedro Marques‐Vidal, Nicholas G. Martin, Colin A. McKenzie, Barbara McKnight, Dan Mellström, Cristina Menni, Grant W. Montgomery, AW Musk, Narisu Narisu, Matthias Nauck, Ilja M. Nolte, Albertine J. Oldehinkel, Matthias Olden, Ken K. Ong, Sandosh Padmanabhan, Patricia A. Peyser, Charlotta Pisinger, David J. Porteous, Olli T. Raitakari, Tuomo Rankinen, D. C. Rao, Laura J. Rasmussen‐Torvik, Rajesh Rawal, Treva Rice, Paul M. Ridker, Lynda M. Rose, Stephanie A. Bien, Igor Rudan, Serena Sanna, Mark A. Sarzynski, Naveed Sattar, Kai Savonen, David Schlessinger, Salome Scholtens, Claudia Schurmann, Robert A. Scott, Bengt Sennblad, Marten A. Siemelink, Günther Silbernagel, P. Eline Slagboom, Harold Snieder, Jan A. Staessen, David J. Stott, Morris A. Swertz, Amy J. Swift, Kent D. Taylor, Bamidele O. Tayo, Barbara Thorand, Dorothée Thuillier, Jaakko Tuomilehto, André G. Uitterlinden, Liesbeth Vandenput, Marie‐Claude Vohl, Henry Völzke, Judith M. Vonk, Gérard Waeber, Mélanie Waldenberger, Rudi G. J. Westendorp, Sarah H. Wild, Gonneke Willemsen, Bruce H. R. Wolffenbuttel, Andrew Wong, Alan F. Wright, Wei Zhao, M. Carola Zillikens, Damiano Baldassarre, Beverley Balkau, Stefania Bandinelli, Carsten A. Böger, Dorret I. Boomsma, Claude Bouchard, Marcel Bruinenberg, Daniel I. Chasman, Yii-DerIda Chen, Peter S. Chines, Francesco Cucca, Daniele Cusi, Ulf dé Fairé, Luigi Ferrucci, Paul W. Franks, Philippe Froguel, Penny Gordon‐Larsen, Hans J. Grabe, Vilmundur Guðnason, Christopher A. Haiman, Caroline Hayward, Kristian Hveem, Andrew D. Johnson, J. Wouter Jukema, Sharon L. R. Kardia, Mika Kivimäki, Jaspal S. Kooner, Diana Kuh, Markku Laakso, Terho Lehtimäki, Loı̈c Le Marchand, Winfried März, Mark I. McCarthy, Andres Metspalu, Andrew P. Morris, Claes Ohlsson, Lyle J. Palmer, Gerard Pasterkamp, Oluf Pedersen, Annette Peters, Ulrike Peters, Ozren Polašek, Bruce M. Psaty, Lu Qi, Rainer Rauramaa, Blair H. Smith, Thorkild I. A. Sørensen, Konstantin Strauch, Henning Tiemeier, Elena Tremoli, Pim van der Harst, Henrik Vestergaard, Péter Vollenweider, Nicholas J. Wareham, David R. Weir, John B. Whitfield, James F. Wilson, Jessica Tyrrell, Timothy M. Frayling, Inês Barroso, Michael Boehnke, Caroline S. Fox, Joel N. Hirschhorn, David J. Hunter, Tim D. Spector, David P. Strachan, Cornelia M. van Duijn, Iris M. Heid, Karen L. Mohlke, Jonathan Marchini, Ruth J. F. Loos, Tuomas O. Kilpeläinen, Ching‐Ti Liu, Ingrid B. Borecki, Kari E. North, L. Adrienne Cupples
Bibliographic record
VenueNature Communications · 2017
Typereview
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenetic Associations and Epidemiology
Canadian institutionsUniversité Laval
FundersFP7 Ideas: European Research CouncilU.S. National Library of MedicineNational Institute of Environmental Health SciencesNational Institute of Mental HealthNational Heart, Lung, and Blood InstituteNational Institute on AgingNational Institute on Alcohol Abuse and AlcoholismFogarty International CenterNational Institutes of HealthHjartaverndMedical Research CouncilTartu ÜlikoolNorwegian Biodiversity Information CentreMedical Research Council CanadaNational Center for Advancing Translational SciencesMagnus Bergvalls StiftelseDanish Agency for Science and Higher EducationMarcus och Amalia Wallenbergs minnesfondHögskolan DalarnaEmil Aaltosen SäätiöFondation LeenaardsDiabetes Research and Wellness FoundationHrvatska Zaklada za ZnanostInstitut National de la Santé et de la Recherche MédicaleMinistero della SaluteKuopion Yliopistollinen SairaalaNational Institute of Diabetes and Digestive and Kidney DiseasesTurun Yliopistollinen KeskussairaalaKnut och Alice Wallenbergs StiftelseNational Center for Research ResourcesNational Institute of General Medical SciencesDiabetesliittoNierstichtingMinisterio de Economía y CompetitividadBritish Heart FoundationBundesministerium für Bildung und ForschungMinistero dell’Istruzione, dell’Università e della RicercaErasmus Universiteit RotterdamNational Health and Medical Research CouncilSuomen KulttuurirahastoStrategiske ForskningsrådZonMwSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungNetherlands Heart InstituteDiabetes FondsFondation LeducqSteno Diabetes Center CopenhagenHealthwayHealth and Safety ExecutiveEuropean Science FoundationEuropean Regional Development FundKing's College LondonJuvenile Diabetes Research Foundation InternationalCanadian Institutes of Health ResearchDiabetes UKNational Human Genome Research InstituteDanmarks Frie ForskningsfondKidney Research UKNational Eye InstituteNational Institute for Health and Care ResearchNational Cancer InstituteAccareDonald W. Reynolds FoundationEli Lilly and CompanyMinistère du Développement Économique, de l’Innovation et de l’ExportationNational Institute on Minority Health and Health DisparitiesErasmus Universitair Medisch Centrum RotterdamLandstinget DalarnasEuropean CommissionCancer Research UKWellcome TrustForsknings- og InnovationsstyrelsenFondation de FranceSundhed og Sygdom, Det Frie ForskningsrådEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentGlaxoSmithKlineAmgenNational Institute on Drug AbuseJohn D. and Catherine T. MacArthur FoundationInterregAndrea and Charles Bronfman PhilanthropiesJuho Vainion SäätiöFoundation for the National Institutes of HealthNovo Nordisk FondenAmerican Heart AssociationBristol-Myers SquibbNederlandse Organisatie voor Wetenschappelijk Onderzoek
KeywordsGenome-wide association studyGeneticsObesityMeta-analysisBiologyComputational biologyGenomeGeneMedicineInternal medicineGenotypeSingle-nucleotide polymorphismEndocrinology
Abstract
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.003
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesMeta-epidemiology (narrow), Research integrity
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Meta-analysis · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: Review
Teacher disagreement score0.768
Threshold uncertainty score1.000
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.004 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 head0.155
GPT teacher head0.415
Teacher spread0.259 · 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 teacher head, not a consensus.
Study designMeta-analysis
Domainnot available
GenreReview
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
Citations233
Published2017
Admission routes2
Has abstractyes