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

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...

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Main Authors: 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 Campbell, 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, 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
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2021
Subjects:
Online Access:https://hdl.handle.net/10356/146952
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-146952
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Smoking
Disease
spellingShingle Science::Medicine
Smoking
Disease
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 Campbell
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
Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
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 Campbell
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
format Article
author 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 Campbell
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
author_sort Erzurumluoglu, A Mesut
title Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
title_short Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
title_full Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
title_fullStr Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
title_full_unstemmed Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
title_sort meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
publishDate 2021
url https://hdl.handle.net/10356/146952
_version_ 1759854509609189376
spelling sg-ntu-dr.10356-1469522023-03-05T16:46:15Z Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci 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 Campbell 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 Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Smoking Disease 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. Published version 2021-03-15T07:59:15Z 2021-03-15T07:59:15Z 2020 Journal Article 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., ...Howson, J. M. M. (2020). Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry, 25(10), 2392-2409. https://dx.doi.org/10.1038/s41380-018-0313-0 1359-4184 https://hdl.handle.net/10356/146952 10.1038/s41380-018-0313-0 30617275 2-s2.0-85059662452 10 25 2392 2409 en Molecular Psychiatry © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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