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Erzurumluoglu, A.M.* ; Liu, M.* ; Jackson, V.E.* ; Barnes, D.R.* ; Datta, G.* ; Melbourne, C.A.* ; Young, R.* ; Batini, C.* ; Surendran, P.* ; Jiang, T.* ; Adnan, S.D.* ; Afaq, S.* ; Agrawal, A.* ; Altmaier, E. ; Antoniou, A.C.* ; Asselbergs, F.W.* ; Baumbach, C. ; Bierut, L.* ; Bertelsen, S.* ; Boehnke, M.* ; Bots, M.L.* ; Brazel, D.M.* ; Chambers, J.C.* ; Chang-Claude, J.* ; Chen, C.* ; Corley, J.* ; Chou, Y.L.* ; David, S.P.* ; de Boer, R.A.* ; de Leeuw, C.A.* ; Dennis, J.G.* ; Dominiczak, A.F.* ; Dunning, A.M.* ; Easton, D.F.* ; Eaton, C.* ; Elliott, P.* ; Evangelou, E.* ; Faul, J.D.* ; Foroud, T.* ; Goate, A.* ; Gong, J.* ; Grabe, H.J.* ; Haessler, J.* ; Haiman, C.* ; Hallmans, G.* ; Hammerschlag, A.R.* ; Harris, S.E.* ; Hattersley, A.* ; Heath, A.* ; Hsu, C.* ; Iacono, W.G.* ; Kanoni, S.* ; Kapoor, M.* ; Kaprio, J.* ; Kardia, S.L.* ; Karpe, F.* ; Kontto, J.* ; Kooner, J.S.* ; Kooperberg, C.* ; Kuulasmaa, K.* ; Laakso, M.* ; Lai, D.* ; Langenberg, C.* ; Le, N.* ; Lettre, G.* ; Loukola, A.* ; Luan, J.* ; Madden, P.A.F.* ; Mangino, M.* ; Marioni, R.E.* ; Marouli, E.* ; Marten, J.* ; Martin, N.G.* ; McGue, M.* ; Michailidou, K.* ; Mihailov, E.* ; Moayyeri, A.* ; Moitry, M.* ; Müller-Nurasyid, M. ; Naheed, A.I.* ; Nauck, M.* ; Neville, M.J.* ; Nielsen, S.F.* ; North, K.* ; Perola, M.* ; Pharoah, P.D.P.* ; Pistis, G.* ; Polderman, T.J.* ; Posthuma, D.* ; Poulter, N.* ; Qaiser, B.* ; Rasheed, A.* ; Reiner, A.* ; Renström, F.* ; Rice, J.* ; Rohde, R.* ; Rolandsson, O.* ; Samani, N.J.* ; Samuel, M.* ; Schlessinger, D.* ; Scholte, S.H.* ; Scott, R.A.* ; Sever, P.* ; Shao, Y.* ; Shrine, N.* ; Smith, J.A.* ; Starr, J.M.* ; Stirrups, K.* ; Stram, D.* ; Stringham, H.M.* ; Tachmazidou, I.* ; Tardif, J.C.* ; Thompson, D.J.* ; Tindle, H.A.* ; Tragante, V.* ; Trompet, S.* ; Turcot, V.* ; Tyrrell, J.* ; Vaartjes, I.* ; van der Leij, A.R.* ; van der Meer, P.* ; Varga, T.V.* ; Verweij, N.* ; Völzke, H.* ; Wareham, N.J.* ; Warren, H.R.* ; Weir, D.R.* ; Weiss, S.* ; Wetherill, L.* ; Yaghootkar, H.* ; Yavas, E.* ; Jiang, Y.* ; Chen, F.* ; Zhan, X.* ; Zhang, W.* ; Zhao, W.* ; Zhou, K.* ; Amouyel, P.* ; Blankenberg, S.* ; Caulfield, M.J.* ; Chowdhury, R.* ; Cucca, F.* ; Deary, I.J.* ; Deloukas, P.* ; di Angelantonio, E.* ; Ferrario, M.* ; Ferrières, J.* ; Franks, P.W.* ; Frayling, T.M.* ; Frossard, P.* ; Hall, I.P.* ; Hayward, C.* ; Jansson, J.H.* ; Jukema, J.W.* ; Kee, F.* ; Männistö, S.* ; Metspalu, A.* ; Munroe, P.B.* ; Nørdestgaard, B.G.* ; Palmer, C.N.A.* ; Salomaa, V.* ; Sattar, N.* ; Spector, T.* ; Strachan, D.P.* ; van der Harst, P.* ; Zeggini, E.* ; Saleheen, D.* ; Butterworth, A.S.* ; Wain, L.V.* ; Abecasis, G.R.* ; Danesh, J.* ; Tobin, M.D.* ; Vrieze, S.* ; Liu, D.J.* ; Howson, J.M.M.*

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

Mol. Psychiatry 25, 2392-2409 (2020)
Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 withP < 5 x 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 x 10(-8)) in the discovery samples. Ten novel SNVs, including rs12616219 nearTMEM182, were followed-up and five of them (rs462779 inREV3L, rs12780116 inCNNM2, rs1190736 inGPR101, rs11539157 inPJA1, and rs12616219 nearTMEM182) replicated at a Bonferroni significance threshold (P < 4.5 x 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, inCCDC141and two low-frequency SNVs inCEP350andHDGFRP2. Functional follow-up implied that decreased expression ofREV3Lmay 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Genome-wide Association; Ld Score Regression; Mendelian Randomization; Lung-cancer; Biological Insights; Cigarette-smoking; Disease; Efficient; Risk; Database
ISSN (print) / ISBN 1359-4184
e-ISSN 1476-5578
Journal Molecular Psychiatry
Quellenangaben Volume: 25, Issue: 10, Pages: 2392-2409 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Grants EC | European Research Council (ERC)
European Research Council
Cancer Research UK
British Heart Foundation (BHF)
British Heart Foundation
NIDDK NIH HHS
NIA NIH HHS
Medical Research Council
Biotechnology and Biological Sciences Research Council