Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Authors: 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, Yun Ju Sung, 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, Jouke Jan Hottenga, Jie Huang, Joseph Hung, Nina Hutri‐Kähönen, Erik Ingelsson, Alan L. James, 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, Richard S. Cooper, 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, Panagiotis Deloukas, 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 - Nature Communications 2017 cited by 233

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.