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 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 C. 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; Goran Hallmans; Peter van der Meer; Niek Verweij; Wei Zhao; Wei Zhao; Pim van der Harst

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 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 C. 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, Goran Hallmans, Peter van der Meer, Niek Verweij, Wei Zhao, Wei Zhao, Pim van der Harst

Cardiovascular Centre (CVC)

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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 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.

Original language	English
Pages (from-to)	2392-2409
Number of pages	18
Journal	Molecular Psychiatry
Volume	25
Issue number	10
DOIs	https://doi.org/10.1038/s41380-018-0313-0
Publication status	Published - Oct-2020

Keywords

GENOME-WIDE ASSOCIATION
LD SCORE REGRESSION
MENDELIAN RANDOMIZATION
LUNG-CANCER
BIOLOGICAL INSIGHTS
CIGARETTE-SMOKING
DISEASE
EFFICIENT
RISK
DATABASE

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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., ... van der Harst, P. (2020). Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry, 25(10), 2392-2409. https://doi.org/10.1038/s41380-018-0313-0

@article{e2a692b0a9b44117a4441c18f5dfa2f6,

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 (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.",

keywords = "GENOME-WIDE ASSOCIATION, LD SCORE REGRESSION, MENDELIAN RANDOMIZATION, LUNG-CANCER, BIOLOGICAL INSIGHTS, CIGARETTE-SMOKING, DISEASE, EFFICIENT, RISK, DATABASE",

author = "Erzurumluoglu, {A. Mesut} and Mengzhen Liu and Jackson, {Victoria E.} and Barnes, {Daniel R.} and Gargi Datta and Melbourne, {Carl A.} and Robin Young 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 C.} 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 Goran Hallmans and {van der Meer}, Peter and Niek Verweij and Wei Zhao and Wei Zhao and {van der Harst}, Pim",

year = "2020",

month = oct,

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

language = "English",

volume = "25",

pages = "2392--2409",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "10",

}

Erzurumluoglu, AM, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, R, 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-L, 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, van der Meer, P, Verweij, N, Zhao, W, Zhao, W & van der Harst, P 2020, 'Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci', Molecular Psychiatry, vol. 25, no. 10, pp. 2392-2409. 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

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 C.

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, Goran

AU - van der Meer, Peter

AU - Verweij, Niek

AU - Zhao, Wei

AU - van der Harst, Pim

PY - 2020/10

Y1 - 2020/10

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 (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.

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 (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.

KW - GENOME-WIDE ASSOCIATION

KW - LD SCORE REGRESSION

KW - MENDELIAN RANDOMIZATION

KW - LUNG-CANCER

KW - BIOLOGICAL INSIGHTS

KW - CIGARETTE-SMOKING

KW - DISEASE

KW - EFFICIENT

KW - RISK

KW - DATABASE

U2 - 10.1038/s41380-018-0313-0

DO - 10.1038/s41380-018-0313-0

M3 - Article

SN - 1359-4184

VL - 25

SP - 2392

EP - 2409

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 10

ER -

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

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