Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
Creators: name: Erzurumluoglu, A. Mesut
name: Liu, Mengzhen
name: Jackson, Victoria E.
name: Barnes, Daniel R.
name: Datta, Gargi
name: Melbourne, Carl A.
name: Young, Robin
name: Batini, Chiara
name: Surendran, Praveen
name: Jiang, Tao
name: Adnan, Sheikh Daud
name: Afaq, Saima
name: Agrawal, Arpana
name: Altmaier, Elisabeth
name: Antoniou, Antonis C.
name: Asselbergs, Folkert W.
name: Baumbach, Clemens
name: Bierut, Laura
name: Bertelsen, Sarah
name: Boehnke, Michael
name: Bots, Michiel L.
name: Brazel, David M
name: Chambers, John C.
name: Chang-Claude, Jenny
name: Chen, Chu
name: Corley, Janie
name: Chou, Yi-Ling
name: David, Sean P.
name: De Boer, Rudolf A.
name: De Leeuw, Christiaan A.
name: Dennis, Joe G.
name: Dominiczak, Anna F.
name: Dunning, Alison M.
name: Easton, Douglas F.
name: Eaton, Charles
name: Elliott, Paul
name: Evangelou, Evangelos
name: Faul, Jessica D.
name: Foroud, Tatiana
name: Goate, Alison
name: Gong, Jian
name: Grabe, Hans J.
name: Haessler, Jeff
name: Haiman, Christopher
name: Hallmans, Göran
name: Hammerschlag, Anke R.
name: Harris, Sarah E.
name: Hattersley, Andrew
name: Heath, Andrew
name: Hsu, Chris
name: Iacono, William G.
name: Kanoni, Stavroula
name: Kapoor, Manav
name: Kaprio, Jaakko
name: Kardia, Sharon L.
name: Karpe, Fredrik
name: Kontto, Jukka
name: Kooner, Jaspal S.
name: Kooperberg, Charles
name: Kuulasmaa, Kari
name: Laakso, Markku
name: Lai, Dongbing
name: Langenberg, Claudia
name: Le, Nhung
name: Lettre, Guillaume
name: Loukola, Anu
name: Luan, Jian’an
name: Madden, Pamela A. F.
name: Mangino, Massimo
name: Marioni, Riccardo E.
name: Marouli, Eirini
name: Marten, Jonathan
name: Martin, Nicholas G.
name: McGue, Matt
name: Michailidou, Kyriaki
name: Mihailov, Evelin
name: Moayyeri, Alireza
name: Moitry, Marie
name: Müller-Nurasyid, Martina
name: Naheed, Aliya
name: Nauck, Matthias
name: Neville, Matthew J.
name: Nielsen, Sune Fallgaard
name: North, Kari
name: Perola, Markus
name: Pharoah, Paul D. P.
name: Pistis, Giorgio
name: Polderman, Tinca J.
name: Posthuma, Danielle
name: Poulter, Neil
name: Qaiser, Beenish
name: Rasheed, Asif
name: Reiner, Alex
name: Renström, Frida
name: Rice, John
name: Rohde, Rebecca
name: Rolandsson, Olov
name: Samani, Nilesh J.
name: Samuel, Maria
name: Schlessinger, David
name: Scholte, Steven H
name: Scott, Robert A.
name: Sever, Peter
name: Shao, Yaming
name: Shrine, Nick
name: Smith, Jennifer A.
name: Starr, John M.
name: Stirrups, Kathleen
name: Stram, Danielle
name: Stringham, Heather M.
name: Tachmazidou, Ioanna
name: Tardif, Jean-Claude
name: Thompson, Deborah J.
name: Tindle, Hilary A.
name: Tragante, Vinicius
name: Trompet, Stella
name: Turcot, Valerie
name: Tyrrell, Jessica
name: Vaartjes, Ilonca
name: Van Der Leij, Andries R
name: Van Der Meer, Peter
name: Varga, Tibor V.
name: Verweij, Niek
name: Völzke, Henry
name: Wareham, Nicholas J.
name: Warren, Helen R.
name: Weir, David R.
name: Weiss, Stefan
name: Wetherill, Leah
name: Yaghootkar, Hanieh
name: Yavas, Ersin
name: Jiang, Yu
name: Chen, Fang
name: Zhan, Xiaowei
name: Zhang, Weihua
name: Zhao, Wei
name: Zhou, Kaixin
name: Amouyel, Philippe
name: Blankenberg, Stefan
name: Caulfield, Mark J.
name: Chowdhury, Rajiv
name: Cucca, Francesco
name: Deary, Ian J.
name: Deloukas, Panos
name: Di Angelantonio, Emanuele
name: Ferrario, Marco
name: Ferrières, Jean
name: Franks, Paul W.
name: Frayling, Tim M.
name: Frossard, Philippe
name: Hall, Ian P.
name: Hayward, Caroline
name: Jansson, Jan-Håkan
name: Jukema, J. Wouter
name: Kee, Frank
name: Männistö, Satu
name: Metspalu, Andres
name: Munroe, Patricia B.
name: Nordestgaard, Børge Grønne
name: Palmer, Colin N. A.
name: Salomaa, Veikko
name: Sattar, Naveed
name: Spector, Timothy
name: Strachan, David Peter
name: Van Der Harst, Pim
name: Zeggini, Eleftheria
name: Saleheen, Danish
name: Butterworth, Adam S.
name: Wain, Louise V.
name: Abecasis, Goncalo R.
name: Danesh, John
name: Tobin, Martin D.
name: Vrieze, Scott
name: Liu, Dajiang J.
name: Howson, Joanna M. M.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2019
Subjects: Article
/631/208
/692/699/476/5
/45/43
/45
article

description: Abstract: 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 &lt; 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 &lt; 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 &lt; 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.