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

A. Mesut Erzurumluoglu; Mengzhen Liu; Victoria E. Jackson; Daniel R. Barnes; Gargi Datta; Carl A. Melbourne; Robin D 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 Campbell 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

doi:10.1038/s41380-018-0313-0

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

A. Mesut Erzurumluoglu, Mengzhen Liu, Victoria E. Jackson, Daniel R. Barnes, Gargi Datta, Carl A. Melbourne, Robin D 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 BoehnkeMichiel L. Bots, David M Brazel, John Campbell 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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 (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<5x10-8 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<5x10-8) 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<4.5x10-3) 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 identification of potential drug targets for smoking prevention and/or cessation.

Original language	English
Journal	Molecular Psychiatry
Early online date	7 Jan 2019
DOIs	https://doi.org/10.1038/s41380-018-0313-0
Publication status	E-pub ahead of print - 7 Jan 2019

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ErzurumluogluMP2018MetaAnalysisAssociatedLociFinal published version, 1.52 MBLicence: Creative Commons: Attribution (CC-BY)

Cite this

Erzurumluoglu, A. M., Liu, M., Jackson, V. E., Barnes, D. R., Datta, G., Melbourne, C. A., Young, R. D., 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., ... Howson, J. M. M. (2019). Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-018-0313-0

@article{cb2a1b147d4b47048e482f0ffb865369,

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

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 (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<5x10-8 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<5x10-8) 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<4.5x10-3) 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 identification of potential drug targets for smoking prevention and/or cessation.",

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

year = "2019",

month = jan,

day = "7",

doi = "10.1038/s41380-018-0313-0",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

}

Erzurumluoglu, AM, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, RD, Batini, C, Surendran, P, Jiang, T, Adnan, SD, Afaq, S, Agrawal, A, Altmaier, E, Antoniou, AC, Asselbergs, FW, Baumbach, C, Bierut, L, Bertelsen, S, Boehnke, M, Bots, ML, Brazel, DM, Chambers, JC, Chang-claude, J, Chen, C, Corley, J, Chou, Y, David, SP, De Boer, RA, De Leeuw, CA, Dennis, JG, Dominiczak, AF, Dunning, AM, Easton, DF, Eaton, C, Elliott, P, Evangelou, E, Faul, JD, Foroud, T, Goate, A, Gong, J, Grabe, HJ, Haessler, J, Haiman, C, Hallmans, G, Hammerschlag, AR, Harris, SE, Hattersley, A, Heath, A, Hsu, C, Iacono, WG, Kanoni, S, Kapoor, M, Kaprio, J, Kardia, SL, Karpe, F, Kontto, J, Kooner, JS, Kooperberg, C, Kuulasmaa, K, Laakso, M, Lai, D, Langenberg, C, Le, N, Lettre, G, Loukola, A, Luan, J, Madden, PAF, Mangino, M, Marioni, RE, Marouli, E, Marten, J, Martin, NG, Mcgue, M, Michailidou, K, Mihailov, E, Moayyeri, A, Moitry, M, Müller-nurasyid, M, Naheed, A, Nauck, M, Neville, MJ, Nielsen, SF, North, K, Perola, M, Pharoah, PDP, Pistis, G, Polderman, TJ, Posthuma, D, Poulter, N, Qaiser, B, Rasheed, A, Reiner, A, Renström, F, Rice, J, Rohde, R, Rolandsson, O, Samani, NJ, Samuel, M, Schlessinger, D, Scholte, SH, Scott, RA, Sever, P, Shao, Y, Shrine, N, Smith, JA, Starr, JM, Stirrups, K, Stram, D, Stringham, HM, Tachmazidou, I, Tardif, J, Thompson, DJ, Tindle, HA, Tragante, V, Trompet, S, Turcot, V, Tyrrell, J, Vaartjes, I, Van Der Leij, AR, Van Der Meer, P, Varga, TV, Verweij, N, Völzke, H, Wareham, NJ, Warren, HR, Weir, DR, Weiss, S, Wetherill, L, Yaghootkar, H, Yavas, E, Jiang, Y, Chen, F, Zhan, X, Zhang, W, Zhao, W, Zhao, W, Zhou, K, Amouyel, P, Blankenberg, S, Caulfield, MJ, Chowdhury, R, Cucca, F, Deary, IJ, Deloukas, P, Di Angelantonio, E, Ferrario, M, Ferrières, J, Franks, PW, Frayling, TM, Frossard, P, Hall, IP, Hayward, C, Jansson, J, Jukema, JW, Kee, F, Männistö, S, Metspalu, A, Munroe, PB, Nordestgaard, BG, Palmer, CNA, Salomaa, V, Sattar, N, Spector, T, Strachan, DP, Van Der Harst, P, Zeggini, E, Saleheen, D, Butterworth, AS, Wain, LV, Abecasis, GR, Danesh, J, Tobin, MD, Vrieze, S, Liu, DJ & Howson, JMM 2019, 'Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci', Molecular Psychiatry. https://doi.org/10.1038/s41380-018-0313-0

TY - JOUR

T1 - Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

AU - Erzurumluoglu, A. Mesut

AU - Liu, Mengzhen

AU - Jackson, Victoria E.

AU - Barnes, Daniel R.

AU - Datta, Gargi

AU - Melbourne, Carl A.

AU - Young, Robin D

AU - Batini, Chiara

AU - Surendran, Praveen

AU - Jiang, Tao

AU - Adnan, Sheikh Daud

AU - Afaq, Saima

AU - Agrawal, Arpana

AU - Altmaier, Elisabeth

AU - Antoniou, Antonis C.

AU - Asselbergs, Folkert W.

AU - Baumbach, Clemens

AU - Bierut, Laura

AU - Bertelsen, Sarah

AU - Boehnke, Michael

AU - Bots, Michiel L.

AU - Brazel, David M

AU - Chambers, John Campbell

AU - Chang-claude, Jenny

AU - Chen, Chu

AU - Corley, Janie

AU - Chou, Yi-ling

AU - David, Sean P.

AU - De Boer, Rudolf A.

AU - De Leeuw, Christiaan A.

AU - Dennis, Joe G.

AU - Dominiczak, Anna F.

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Eaton, Charles

AU - Elliott, Paul

AU - Evangelou, Evangelos

AU - Faul, Jessica D.

AU - Foroud, Tatiana

AU - Goate, Alison

AU - Gong, Jian

AU - Grabe, Hans J.

AU - Haessler, Jeff

AU - Haiman, Christopher

AU - Hallmans, Göran

AU - Hammerschlag, Anke R.

AU - Harris, Sarah E.

AU - Hattersley, Andrew

AU - Heath, Andrew

AU - Hsu, Chris

AU - Iacono, William G.

AU - Kanoni, Stavroula

AU - Kapoor, Manav

AU - Kaprio, Jaakko

AU - Kardia, Sharon L.

AU - Karpe, Fredrik

AU - Kontto, Jukka

AU - Kooner, Jaspal S.

AU - Kooperberg, Charles

AU - Kuulasmaa, Kari

AU - Laakso, Markku

AU - Lai, Dongbing

AU - Langenberg, Claudia

AU - Le, Nhung

AU - Lettre, Guillaume

AU - Loukola, Anu

AU - Luan, Jian’an

AU - Madden, Pamela A. F.

AU - Mangino, Massimo

AU - Marioni, Riccardo E.

AU - Marouli, Eirini

AU - Marten, Jonathan

AU - Martin, Nicholas G.

AU - Mcgue, Matt

AU - Michailidou, Kyriaki

AU - Mihailov, Evelin

AU - Moayyeri, Alireza

AU - Moitry, Marie

AU - Müller-nurasyid, Martina

AU - Naheed, Aliya

AU - Nauck, Matthias

AU - Neville, Matthew J.

AU - Nielsen, Sune Fallgaard

AU - North, Kari

AU - Perola, Markus

AU - Pharoah, Paul D. P.

AU - Pistis, Giorgio

AU - Polderman, Tinca J.

AU - Posthuma, Danielle

AU - Poulter, Neil

AU - Qaiser, Beenish

AU - Rasheed, Asif

AU - Reiner, Alex

AU - Renström, Frida

AU - Rice, John

AU - Rohde, Rebecca

AU - Rolandsson, Olov

AU - Samani, Nilesh J.

AU - Samuel, Maria

AU - Schlessinger, David

AU - Scholte, Steven H

AU - Scott, Robert A.

AU - Sever, Peter

AU - Shao, Yaming

AU - Shrine, Nick

AU - Smith, Jennifer A.

AU - Starr, John M.

AU - Stirrups, Kathleen

AU - Stram, Danielle

AU - Stringham, Heather M.

AU - Tachmazidou, Ioanna

AU - Tardif, Jean-claude

AU - Thompson, Deborah J.

AU - Tindle, Hilary A.

AU - Tragante, Vinicius

AU - Trompet, Stella

AU - Turcot, Valerie

AU - Tyrrell, Jessica

AU - Vaartjes, Ilonca

AU - Van Der Leij, Andries R

AU - Van Der Meer, Peter

AU - Varga, Tibor V.

AU - Verweij, Niek

AU - Völzke, Henry

AU - Wareham, Nicholas J.

AU - Warren, Helen R.

AU - Weir, David R.

AU - Weiss, Stefan

AU - Wetherill, Leah

AU - Yaghootkar, Hanieh

AU - Yavas, Ersin

AU - Jiang, Yu

AU - Chen, Fang

AU - Zhan, Xiaowei

AU - Zhang, Weihua

AU - Zhao, Wei

AU - Zhou, Kaixin

AU - Amouyel, Philippe

AU - Blankenberg, Stefan

AU - Caulfield, Mark J.

AU - Chowdhury, Rajiv

AU - Cucca, Francesco

AU - Deary, Ian J.

AU - Deloukas, Panos

AU - Di Angelantonio, Emanuele

AU - Ferrario, Marco

AU - Ferrières, Jean

AU - Franks, Paul W.

AU - Frayling, Tim M.

AU - Frossard, Philippe

AU - Hall, Ian P.

AU - Hayward, Caroline

AU - Jansson, Jan-håkan

AU - Jukema, J. Wouter

AU - Kee, Frank

AU - Männistö, Satu

AU - Metspalu, Andres

AU - Munroe, Patricia B.

AU - Nordestgaard, Børge Grønne

AU - Palmer, Colin N. A.

AU - Salomaa, Veikko

AU - Sattar, Naveed

AU - Spector, Timothy

AU - Strachan, David Peter

AU - Van Der Harst, Pim

AU - Zeggini, Eleftheria

AU - Saleheen, Danish

AU - Butterworth, Adam S.

AU - Wain, Louise V.

AU - Abecasis, Goncalo R.

AU - Danesh, John

AU - Tobin, Martin D.

AU - Vrieze, Scott

AU - Liu, Dajiang J.

AU - Howson, Joanna M. M.

PY - 2019/1/7

Y1 - 2019/1/7

N2 - 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 (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<5x10-8 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<5x10-8) 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<4.5x10-3) 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 identification of potential drug targets for smoking prevention and/or cessation.

AB - 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 (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<5x10-8 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<5x10-8) 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<4.5x10-3) 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 identification of potential drug targets for smoking prevention and/or cessation.

UR - https://static-content.springer.com/esm/art%3A10.1038%2Fs41380-018-0313-0/MediaObjects/41380_2018_313_MOESM1_ESM.docx

U2 - 10.1038/s41380-018-0313-0

DO - 10.1038/s41380-018-0313-0

M3 - Article

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

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The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

Stratifying Resilience and Depression Longitudinally

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

Abstract / Description of output

Access to Document

Other files and links

Fingerprint

Projects

The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

Stratifying Resilience and Depression Longitudinally

Cite this