Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
Authors:   Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium, Erzurumluoglu A. Mesut , Liu Mengzhen , Jackson Victoria E. , Barnes Daniel R. , Datta Gargi , Melbourne Carl A. , Young Robin , Batini Chiara , Surendran Praveen , Jiang Tao , Adnan Sheikh Daud , Afaq Saima , Agrawal Arpana , Altmaier Elisabeth , Antoniou Antonis C. , Asselbergs Folkert W. , Baumbach Clemens , Bierut Laura , Bertelsen Sarah , Boehnke Michael , Bots Michiel L. , Brazel David M , Chambers John C. , Chang-Claude Jenny , Chen Chu , Corley Janie , Chou Yi-Ling , David Sean P. , de Boer Rudolf A. , de Leeuw Christiaan A. , Dennis Joe G. , Dominiczak Anna F. , Dunning Alison M. , Easton Douglas F. , Eaton Charles , Elliott Paul , Evangelou Evangelos , Faul Jessica D. , Foroud Tatiana , Goate Alison , Gong Jian , Grabe Hans J. , Haessler Jeff , Haiman Christopher , Hallmans Göran , Hammerschlag Anke R. , Harris Sarah E. , Hattersley Andrew , Heath Andrew , Hsu Chris , Iacono William G. , Kanoni Stavroula , Kapoor Manav , Kaprio Jaakko , Kardia Sharon L. , Karpe Fredrik , Kontto Jukka , Kooner Jaspal S. , Kooperberg Charles , Kuulasmaa Kari , Laakso Markku , Lai Dongbing , Langenberg Claudia , Le Nhung , Lettre Guillaume , Loukola Anu , Luan Jian’an , Madden Pamela A. F. , Mangino Massimo , Marioni Riccardo E. , Marouli Eirini , Marten Jonathan , Martin Nicholas G. , McGue Matt , Michailidou Kyriaki , Mihailov Evelin , Moayyeri Alireza , Moitry Marie , Müller-Nurasyid Martina , Naheed Aliya , Nauck Matthias , Neville Matthew J. , Nielsen Sune Fallgaard , North Kari , Perola Markus , Pharoah Paul D. P. , Pistis Giorgio , Polderman Tinca J. , Posthuma Danielle , Poulter Neil , Qaiser Beenish , Rasheed Asif , Reiner Alex , Renström Frida , Rice John , Rohde Rebecca , Rolandsson Olov , Samani Nilesh J. , Samuel Maria , Schlessinger David , Scholte Steven H , Scott Robert A. , Sever Peter , Shao Yaming , Shrine Nick , Smith Jennifer A. , Starr John M. , Stirrups Kathleen , Stram Danielle , Stringham Heather M. , Tachmazidou Ioanna , Tardif Jean-Claude , Thompson Deborah J. , Tindle Hilary A. , Tragante Vinicius , Trompet Stella , Turcot Valerie , Tyrrell Jessica , Vaartjes Ilonca , van der Leij Andries R , van der Meer Peter , Varga Tibor V. , Verweij Niek , Völzke Henry , Wareham Nicholas J. , Warren Helen R. , Weir David R. , Weiss Stefan , Wetherill Leah , Yaghootkar Hanieh , Yavas Ersin , Jiang Yu , Chen Fang , Zhan Xiaowei , Zhang Weihua , Zhao Wei , Zhao Wei , Zhou Kaixin , Amouyel Philippe , Blankenberg Stefan , Caulfield Mark J. , Chowdhury Rajiv , Cucca Francesco , Deary Ian J. , Deloukas Panos , Di Angelantonio Emanuele , Ferrario Marco , Ferrières Jean , Franks Paul W. , Frayling Tim M. , Frossard Philippe , Hall Ian P. , Hayward Caroline , Jansson Jan-Håkan , Jukema J. Wouter , Kee Frank , Männistö Satu , Metspalu Andres , Munroe Patricia B. , Nordestgaard Børge Grønne , Palmer Colin N. A. , Salomaa Veikko , Sattar Naveed , Spector Timothy , Strachan David Peter , van der Harst Pim , Zeggini Eleftheria , Saleheen Danish , Butterworth Adam S. , Wain Louise V. , Abecasis Goncalo R. , Danesh John , Tobin Martin D. , Vrieze Scott , Liu Dajiang J. , Howson Joanna M. M. 
Published: January 2019

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.