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.

Authors	Justice, Anne E.; Winkler, Thomas W.; Feitosa, Mary F.; Graff, Misa; Fisher, Virginia A.; Young, Kristin; Barata, Llilda; Deng, Xuan; Czajkowski, Jacek; Hadley, David; Ngwa, Julius S.; Ahluwalia, Tarunveer S.; Chu, Audrey Y.; Heard-Costa, Nancy L.; Lim, Elise; Perez, Jeremiah; Eicher, John D.; Kutalik, Zoltan; Xue, Luting; Mahajan, Anubha; Renstrom, Frida; Wu, Joseph; Qi, Qibin; Ahmad, Shafqat; Alfred, Tamuno; Amin, Najaf; Bielak, Lawrence F.; Bonnefond, Amelie; Bragg, Jennifer; Cadby, Gemma; Chittani, Martina; Coggeshall, Scott; Corre, Tanguy; Direk, Nese; Eriksson, Joel; Fischer, Krista; Gorski, Mathias; Harder, Marie Neergaard; Horikoshi, Momoko; Huang, Tao; Huffman, Jennifer E.; Jackson, Anne U.; Justesen, Johanne Marie; Kanoni, Stavroula; Kinnunen, Leena; Kleber, Marcus E.; Komulainen, Pirjo; Kumari, Meena; Lim, Unhee; Luan, Jian'an; Lyytikainen, Leo-Pekka; Mangino, Massimo; Manichaikul, Ani; Marten, Jonathan; Middelberg, Rita P. S.; Mueller-Nurasyid, Martina; Navarro, Pau; Perusse, Louis; Pervjakova, Natalia; Sarti, Cinzia; Smith, Albert Vernon; Smith, Jennifer A.; Stancakova, Alena; Strawbridge, Rona J.; Stringham, Heather M.; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W.; van der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Vedantam, Sailaja L.; Verweij, Niek; Vink, Jacqueline M.; Vitart, Veronique; Wu, Ying; Yengo, Loic; Zhang, Weihua; Zhao, JH; Zimmermann, Martina E.; Zubair, Niha; Abecasis, Goncalo R.; Adair, Linda S.; Afaq, Saima; Afzal, Uzma; Bakker, Stephan J. L.; Bartz, Traci M.; Beilby, John; Bergman, Richard N.; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boerwinkle, Eric; Bonnycastle, Lori L.; Bottinger, Erwin; Braga, Daniele; Buckley, Brendan M.; Buyske, Steve; Campbell, Harry; Chambers, John C.; Collins, FS; Curran, Joanne E.; de Borst, Gert J.; de Craen, Anton J. M.; de Geus, Eco J. C.; Dedoussis, George; Delgado, Graciela E.; den Ruijter, Hester M.; Eiriksdottir, Gudny; Eriksson, Anna L.; Esko, Tonu; Faul, Jessica D.; Ford, Ian; Forrester, Terrence; Gertow, Karl; Gigante, Bruna; Glorioso, Nicola; Gong, Jian; Grallert, Harald; Grammer, Tanja B.; Grarup, Niels; Haitjema, Saskia; Hallmans, Goran; Hamsten, Anders; Hansen, Torben; Harris, Tamara B.; Hartman, Catharina A.; Hassinen, Maija; Hastie, Nicholas D.; Heath, Andrew C.; Hernandez, Dena; Hindorff, Lucia; Hocking, Lynne J.; Hollensted, Mette; Holmen, Oddgeir L.; Homuth, Georg; Hottenga, Jouke Jan; Huang, Jie; Hung, Joseph; Hutri-Kahonen, Nina; Ingelsson, Erik; James, Alan L.; Jansson, John-Olov; Jarvelin, Marjo-Riitta; Jhun, Min A.; Jorgensen, Marit E.; Juonala, Markus; Kahonen, Mika; Karlsson, Magnus; Koistinen, Heikki A.; Kolcic, Ivana; Kolovou, Genovefa; Kooperberg, Charles; Kramer, Bernhard K.; Kuusisto, Johanna; Kvaloy, Kirsti; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Leander, Karin; Lee, Nanette R.; Lind, Lars; Lindgren, Cecilia M.; Linneberg, Allan; Lobbens, Stephane; Loh, Marie; Lorentzon, Mattias; Luben, Robert; Lubke, Gitta; Ludolph-Donislawski, Anja; Lupoli, Sara; Madden, Pamela A. F.; Mannikko, Reija; Marques-Vidal, Pedro; Martin, Nicholas G.; McKenzie, Colin A.; McKnight, Barbara; Mellstrom, Dan; Menni, Cristina; Montgomery, Grant W.; Musk, A. W. (Bill); Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M.; Oldehinkel, Albertine J.; Olden, Matthias; Ong, Ken K.; Padmanabhan, Sandosh; Peyser, Patricia A.; Pisinger, Charlotta; Porteous, David J.; Raitakari, Olli T.; Rankinen, Tuomo; Rao, D. C.; Rasmussen-Torvik, Laura J.; Rawal, Rajesh; Rice, Treva; Ridker, Paul M.; Rose, Lynda M.; Bien, Stephanie A.; Rudan, Igor; Sanna, Serena; Sarzynski, Mark A.; Sattar, Naveed; Savonen, Kai; Schlessinger, David; Scholtens, Salome; Schurmann, Claudia; Scott, Robert A.; Sennblad, Bengt; Siemelink, Marten A.; Silbernagel, Gunther; Slagboom, E; Snieder, Harold; Staessen, Jan A.; Stott, David J.; Swertz, Morris A.; Swift, Amy J.; Taylor, Kent D.; Tayo, Bamidele O.; Thorand, Barbara; Thuillier, Dorothee; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vandenput, Liesbeth; Vohl, Marie-Claude; Volzke, Henry; Vonk, Judith M.; Waeber, Gerard; Waldenberger, Melanie; Westendorp, R. G. J.; Wild, Sarah; Willemsen, Gonneke; Wolffenbuttel, Bruce H. R.; Wong, Andrew; Wright, Alan F.; Zhao, Wei; Zillikens, M. Carola; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Boger, Carsten A.; Boomsma, Dorret I.; Bouchard, Claude; Bruinenberg, Marcel; Chasman, Daniel I.; Chen, Yii-Der Ida; Chines, Peter S.; Cooper, Richard S.; Cucca, Francesco; Cusi, Daniele; de Faire, Ulf; Ferrucci, Luigi; Franks, Paul W.; Froguel, Philippe; Gordon-Larsen, Penny; Grabe, Hans-Jorgen; Gudnason, Vilmundur; Haiman, Christopher A.; Hayward, Caroline; Hveem, Kristian; Johnson, Andrew D.; Jukema, Wouter; Kardia, Sharon L. R.; Kivimaki, Mika; Kooner, Jaspal S.; Kuh, Diana; Laakso, Markku; Lehtimaki, Terho; Le Marchand, Loic; Marz, Winfried; McCarthy, Mark I.; Metspalu, A; Morris, Andrew P.; Ohlsson, Claes; Palmer, Lyle J.; Pasterkamp, Gerard; Pedersen, Oluf; Peters, Annette; Peters, Ulrike; Polasek, Ozren; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Smith, Blair H.; Sorensen, Thorkild I. A.; Strauch, Konstantin; Tiemeier, Henning; Tremoli, Elena; Van der Harst, Pim; Vestergaard, Henrik; Vollenweider, Peter; Wareham, Nicholas J.; Weir, David R.; Whitfield, John B.; Wilson, James F.; Tyrrell, Jessica; Frayling, Timothy M.; Barroso, Ines; Boehnke, Michael; Deloukas, Panagiotis; Fox, Caroline S.; Hirschhorn, Joel N.; Hunter, David J.; Spector, Tim D.; Strachan, David P.; van Duijn, Cornelia M.; Heid, Iris M.; Mohlke, Karen L.; Marchini, Jonathan; Loos, Ruth J. F.; Kilpelainen, Tuomas O.; Liu, Ching-Ti; Borecki, Ingrid B.; North, Kari E.; Cupples, L. Adrienne
Journal	Nature Communications
Pages
Volume	8
Date	1/04/2017
Grant ID
Funding Body	Aase and Ejner Danielsens Foundation
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/ncomms14977