Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

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Journal Article

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Molecular Psychiatry


A. Mesut Erzurumluoglu, MengZhen Liu, Victoria E. Jackson, Daniel R. Barnes, Gauri Datta, Carl A. Melbourne, Robin Young, Chiara Batini, Praveen Surendran, Tao Jiang, Sheikh Daud Adnan, Saima Afaq, Arpana Agrawal, Elisabeth Altmaier, Antonis C. Antoniou, Folkert W. Asselbergs, Clemens Baumbach, Laura Bierut, Sarah Bertelsen, Michael Boehnke, Michiel L. Bots, David M. Brazel, John C. Chambers, Jenny Chang-Claude, Chu Chen, Janie Corley, Yi-Ling Chou, Sean P. David, Rudolf A. de Boer, Christiaan A. de Leeuw, Joe G. Dennis, Anna F. Dominiczak, Alison M. Dunning, Douglas F. Easton, Charles Eaton, Paul Elliott, Evangelos Evangelou, Jessica D. Faul, Tatiana Foroud, Alison Goate, Jian Gong, Hans J. Grabe, Jeff Haessler, Christopher Haiman, Göran Hallmans, Anke R. Hammerschlag, Sarah E. Harris, Andrew Hattersley, Andrew Heath, Chris Hsu, William G. Iacono, Stavroula Kanoni, Manav Kapoor, Jaakko Kaprio, Sharon L. Kardia, Fredrik Karpe, Jukka Kontto, Jaspal S. Kooner, Charles Kooperberg, Kari Kuulasmaa, Markku Laakso, Dongbing Lai, Claudia Langenberg, Nhung Le, Guillaume Lettre, Anu Loukola, Jian’an Luan, Pamela A.F. Madden, Massimo Mangino, Riccardo E. Marioni, Eirini Marouli, Jonathan Marten, Nicholas G. Martin, Matt McGue, Kyriaki Michailidou, Evelin Mihailov, Alireza Moayyeri, Marie Moitry, Martina Müller-Nurasyid, Aliya Naheed, Matthias Nauck, Matthew J. Neville, Sune Fallgaard Nielsen, Kari North, Markus Perola, Paul D. P. Pharoah, Giorgio Pistis, Tinca J. Polderman, Danielle Posthuma, Neil Poulter, Beenish Qaiser, Asif Rasheed, Alex Reiner, Frida Renström, John Rice, Rebecca Rohde, Olov Rolandsson, Nilesh J. Samani, Maria Samuel, David Schlessinger, Steven H. Scholte, Robert A. Scott, Peter Sever, Yaming Shao, Nick Shrine, Jennifer A. Smith, John M. Starr, Kathleen Stirrups, Danielle Stram, Heather M. Stringham, Ioanna Tachmazidou, Jean-Claude Tardif, Deborah J. Thompson, Hilary A. Tindle, Vinicius Tragante, Stella Trompet, Valérie Turcot, Jessica Tyrrell, Ilonca Vaartjes, Andries R. van der Leij, Peter van der Meer, Tibor V. Varga, Niek Verweij, Henry Völzke, Nicholas J. Wareham, Helen R. Warren, David R. Weir, Stefan Weiss, Leah Wetherill, Hanieh Yaghootkar, Ersin Yavas, Yu Jiang, Fang Chen, Xiaowei Zhan, Weihua Zhang, Wei Zhao, Kaixin Zhou, Philippe Amouyel, Stefan Blankenberg, Mark J. Caulfield, Rajiv Chowdhury, Francesco Cucca, Ian J. Deary, Panos Deloukas, Emanuele Di Angelantonio, Marco Ferrario, Jean Ferrières, Paul W. Franks, Tim M. Frayling, Philippe Frossard, Ian P. Hall, Caroline Hayward, Jan-Håkan Jansson, J. Wouter Jukema, Frank Kee, Satu Männistö, Andres Metspalu, Patricia B. Munroe, Børge Grønne Nordestgaard, Colin N. A. Palmer, Veikko Salomaa, Naveed Sattar, Timothy Spector, David Peter Strachan, Pim van der Harst, Eleftheria Zeggini, Danish Saleheen, Adam S. Butterworth, Louise V. Wain, Goncalo R. Abecasis, John Danesh, Martin D. Tobin, Scott Vrieze, Dajiang J. Liu and Joanna M. M. Howson

Publication date


Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.





Health, Biology and Genetics


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