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

Authors:
Saima Afaq
Saima Afaq
Institute of Public health and Social Sciences, Khyber medical university Peshawar Pakistan
Dr
Peshawar, KPK | Pakistan
A Mesut Erzurumluoglu Mengzhen Liu Victoria E Jackson Daniel R Barnes Gargi Datta Carl A Melbourne Robin Young Chiara Batini Praveen Surendran Tao Jiang Sheikh Daud Adnan 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 Valerie 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 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 Joanna M M Howson

Mol Psychiatry 2019 Jan 7. Epub 2019 Jan 7.

MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.

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 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) 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) 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.

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http://www.nature.com/articles/s41380-018-0313-0
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http://dx.doi.org/10.1038/s41380-018-0313-0DOI Listing
January 2019
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