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

A Mesut Erzurumluoglu^#¹, Mengzhen Liu^#², Victoria E Jackson^#^{1

3

4}, Daniel R Barnes⁵, Gargi Datta^{2

6}, Carl A Melbourne¹, Robin Young⁵, Chiara Batini¹, Praveen Surendran⁵, Tao Jiang⁵, Sheikh Daud Adnan⁷, Saima Afaq⁸, Arpana Agrawal⁹, Elisabeth Altmaier¹⁰, Antonis C Antoniou¹¹, Folkert W Asselbergs^{12

13

14

15}, Clemens Baumbach¹⁰, Laura Bierut¹⁶, Sarah Bertelsen¹⁷, Michael Boehnke¹⁸, Michiel L Bots^{19

20}, David M Brazel^{6

21}, John C Chambers^{8

22

23

24}, Jenny Chang-Claude^{25

26}, Chu Chen^{27

28}, Janie Corley^{29

30}, Yi-Ling Chou⁹, Sean P David³¹, Rudolf A de Boer³², Christiaan A de Leeuw³³, Joe G Dennis¹¹, Anna F Dominiczak³⁴, Alison M Dunning³⁵, Douglas F Easton^{11

35}, Charles Eaton²⁸, Paul Elliott^{36

37

38

39}, Evangelos Evangelou^{8

40}, Jessica D Faul⁴¹, Tatiana Foroud⁴², Alison Goate¹⁷, Jian Gong²⁷, Hans J Grabe⁴³, Jeff Haessler²⁷, Christopher Haiman⁴⁴, Göran Hallmans⁴⁵, Anke R Hammerschlag³³, Sarah E Harris^{29

46}, Andrew Hattersley⁴⁷, Andrew Heath⁹, Chris Hsu⁴⁸, William G Iacono², Stavroula Kanoni^{49

50}, Manav Kapoor¹⁷, Jaakko Kaprio^{51

52}, Sharon L Kardia⁵³, Fredrik Karpe^{54

55}, Jukka Kontto⁵⁶, Jaspal S Kooner^{23

24

37

57}, Charles Kooperberg^{27

58}, Kari Kuulasmaa⁵⁶, Markku Laakso⁵⁹, Dongbing Lai⁴², Claudia Langenberg⁶⁰, Nhung Le⁶¹, Guillaume Lettre^{62

63}, Anu Loukola^{51

52}, Jian'an Luan⁶⁰, Pamela A F Madden⁹, Massimo Mangino^{64

65}, Riccardo E Marioni^{29

46}, Eirini Marouli^{49

50}, Jonathan Marten⁶⁶, Nicholas G Martin⁶⁷, Matt McGue², Kyriaki Michailidou^{11

68}, Evelin Mihailov⁶⁹, Alireza Moayyeri⁷⁰, Marie Moitry⁷¹, Martina Müller-Nurasyid^{72

73

74}, Aliya Naheed⁷⁵, Matthias Nauck^{76

77}, Matthew J Neville^{54

55}, Sune Fallgaard Nielsen⁷⁸, Kari North⁷⁹, Markus Perola^{51

56}, Paul D P Pharoah^{11

35}, Giorgio Pistis⁸⁰, Tinca J Polderman³³, Danielle Posthuma^{33

81}, Neil Poulter⁸², Beenish Qaiser^{51

52}, Asif Rasheed⁸³, Alex Reiner^{28

27}, Frida Renström^{84

85}, John Rice⁸⁶, Rebecca Rohde⁸⁷, Olov Rolandsson⁸⁸, Nilesh J Samani⁸⁹, Maria Samuel⁸³, David Schlessinger⁹⁰, Steven H Scholte⁹¹, Robert A Scott⁶⁰, Peter Sever^{57

82}, Yaming Shao⁸⁷, Nick Shrine¹, Jennifer A Smith⁵³, John M Starr^{29

92}, Kathleen Stirrups^{49

93}, Danielle Stram⁹⁴, Heather M Stringham¹⁸, Ioanna Tachmazidou⁹⁵, Jean-Claude Tardif^{62

63}, Deborah J Thompson¹¹, Hilary A Tindle⁹⁶, Vinicius Tragante⁹⁷, Stella Trompet^{98

99}, Valerie Turcot⁶², Jessica Tyrrell⁴⁷, Ilonca Vaartjes^{19

20}, Andries R van der Leij⁹¹, Peter van der Meer³², Tibor V Varga⁸⁴, Niek Verweij^{32

100}, Henry Völzke^{77

101}, Nicholas J Wareham⁶⁰, Helen R Warren^{102

103}, David R Weir⁴¹, Stefan Weiss^{77

104}, Leah Wetherill⁴², Hanieh Yaghootkar⁴⁷, Ersin Yavas^{105

106}, Yu Jiang¹⁰⁷, Fang Chen¹⁰⁷, Xiaowei Zhan¹⁰⁸, Weihua Zhang^{8

109}, Wei Zhao¹¹⁰, Wei Zhao⁵³, Kaixin Zhou¹¹¹, Philippe Amouyel¹¹², Stefan Blankenberg^{113

114}, Mark J Caulfield^{102

103}, Rajiv Chowdhury⁵, Francesco Cucca⁸⁰, Ian J Deary^{29

30}, Panos Deloukas^{95

49

115}, Emanuele Di Angelantonio^{5

116}, Marco Ferrario¹¹⁷, Jean Ferrières¹¹⁸, Paul W Franks^{84

119}, Tim M Frayling⁴⁷, Philippe Frossard⁸³, Ian P Hall¹²⁰, Caroline Hayward⁶⁶, Jan-Håkan Jansson¹²¹, J Wouter Jukema^{122

123}, Frank Kee¹²⁴, Satu Männistö⁵⁶, Andres Metspalu⁶⁹, Patricia B Munroe^{102

103}, Børge Grønne Nordestgaard⁷⁸, Colin N A Palmer¹²⁵, Veikko Salomaa⁵⁶, Naveed Sattar¹²⁶, Timothy Spector⁶⁵, David Peter Strachan¹²⁷; Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium; Pim van der Harst^{32

128}, Eleftheria Zeggini⁹⁵, Danish Saleheen^{5

129

130}, Adam S Butterworth^{5

116}, Louise V Wain^{1

131}, Goncalo R Abecasis¹⁸, John Danesh^{5

95

116}, Martin D Tobin^#^{1

131}, Scott Vrieze^#², Dajiang J Liu^#¹³², Joanna M M Howson^#¹³³

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK.
² Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
³ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, 3052, Parkville, Australia.
⁴ Department of Medical Biology, University of Melbourne, Melbourne, 3010, Parkville, Australia.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁷ National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
⁹ Department of Psychiatry, Washington University, St. Louis, MO, USA.
¹⁰ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
¹² Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
¹³ Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
¹⁴ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁵ Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK.
¹⁶ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹⁷ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508GA, Utrecht, The Netherlands.
²⁰ Center for Circulatory Health, University Medical Center Utrecht, 3508GA, Utrecht, The Netherlands.
²¹ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
²² Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
²³ Department of Cardiology, Ealing Hospital, Middlesex, UB1 3HW, UK.
²⁴ Imperial College Healthcare NHS Trust, London, W12 0HS, UK.
²⁵ Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
²⁶ Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
²⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁸ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³⁰ Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³¹ Department of Medicine, Stanford University, Stanford, CA, USA.
³² Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³³ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.
³⁴ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge Centre, University of Cambridge, Cambridge, CB1 8RN, UK.
³⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
³⁷ MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK.
³⁸ National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust and Imperial College London, London, UK.
³⁹ UK Dementia Research Institute (UK DRI) at Imperial College London, London, UK.
⁴⁰ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁴¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁴² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475, Greifswald, Germany.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁴⁵ Department of Public Health and Clinical Medicine, Nutritional research, Umeå University, Umeå, Sweden.
⁴⁶ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
⁴⁷ Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
⁴⁸ University of Southern California, California, CA, USA.
⁴⁹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
⁵⁰ Centre for Genomic Health, Queen Mary University of London, London, EC1M 6BQ, UK.
⁵¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁵² Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
⁵⁵ Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, UK.
⁵⁶ Department of Public Health Solutions, National Institute for Health and Welfare, FI-00271, Helsinki, Finland.
⁵⁷ National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK.
⁵⁸ Department of Biostatistics, University of Washington School of Medicine, Seattle, WA, USA.
⁵⁹ University of Eastern Finland, Finland, Finland.
⁶⁰ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
⁶¹ Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
⁶² Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
⁶³ Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, H3T 1J4, Canada.
⁶⁴ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, SE1 9RT, UK.
⁶⁵ Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
⁶⁶ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶⁷ Queensland Institute for Medical Research, Brisbane, Australia.
⁶⁸ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.
⁶⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁷⁰ Institute of Health Informatics, University College London, London, UK.
⁷¹ Department of Epidemiology and Public health, University Hospital of Strasbourg, Strasbourg, France.
⁷² Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷³ Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
⁷⁴ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
⁷⁵ Initiative for Noncommunicable Diseases, Health Systems and Population Studies Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
⁷⁶ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
⁷⁷ DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Greifswald, Germany.
⁷⁸ Department of Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 74, DK-2730, Herlev, Denmark.
⁷⁹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁸⁰ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
⁸¹ Department of Clinical Genetics, VU University Medical Centre Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
⁸² International Centre for Circulatory Health, Imperial College London, London, UK.
⁸³ Centre for Non-Communicable Diseases, Karachi, Pakistan.
⁸⁴ Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital, Lund University, SE-214 28, Malmö, Sweden.
⁸⁵ Department of Biobank Research, Umeå University, SE-901 87, Umeå, Sweden.
⁸⁶ Departments of Psychiatry and Mathematics, Washington University St. Louis, St. Louis, MO, USA.
⁸⁷ University of North Carolina, Chapel Hill, NC, USA.
⁸⁸ Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE, 90185, Umeå, Sweden.
⁸⁹ Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
⁹⁰ National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁹¹ Department of Psychology, University of Amsterdam & Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, Netherlands.
⁹² Alzheimer Scotland Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁹³ Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK.
⁹⁴ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹⁵ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁹⁶ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁹⁷ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, 3508GA, Utrecht, The Netherlands.
⁹⁸ Department of gerontology and geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁹ Department of cardiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA, 02142, USA.
¹⁰¹ Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
¹⁰² Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰³ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰⁴ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17475, Greifswald, Germany.
¹⁰⁵ Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.
¹⁰⁶ Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, PA, 16802, USA.
¹⁰⁷ Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA.
¹⁰⁸ Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, TX, USA.
¹⁰⁹ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
¹¹⁰ Department of Biostatistics and Epidemiology, University of Pennsylvania, Pennsylvania, PA, USA.
¹¹¹ School of Medicine, University of Dundee, Dundee, UK.
¹¹² Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France.
¹¹³ Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
¹¹⁴ University Medical Center Hamburg Eppendorf, Hamburg, Germany.
¹¹⁵ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
¹¹⁶ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
¹¹⁷ EPIMED Research Centre, Department of Medicine and Surgery, University of Insubria at Varese, Varese, Italy.
¹¹⁸ Department of Epidemiology, UMR 1027- INSERM, Toulouse University-CHU Toulouse, Toulouse, France.
¹¹⁹ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
¹²⁰ Division of Respiratory Medicine and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
¹²¹ Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden.
¹²² Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
¹²³ The Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
¹²⁴ UKCRC Centre of Excellence for Public Health, Queens, University, Belfast, Belfast, UK.
¹²⁵ Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
¹²⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹²⁷ Population Health Research Institute, St George!s, University of London, London, SW17 0RE, UK.
¹²⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹²⁹ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
¹³⁰ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹³¹ National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
¹³² Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA. dxl46@psu.edu.
¹³³ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. jmmh2@medschl.cam.ac.uk.

^# Contributed equally.

PMID: 30617275
PMCID: PMC7515840
DOI: 10.1038/s41380-018-0313-0

Meta-Analysis

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

A Mesut Erzurumluoglu et al. Mol Psychiatry. 2020 Oct.

. 2020 Oct;25(10):2392-2409.

doi: 10.1038/s41380-018-0313-0. Epub 2019 Jan 7.

Authors

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, UK.
² Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
³ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, 3052, Parkville, Australia.
⁴ Department of Medical Biology, University of Melbourne, Melbourne, 3010, Parkville, Australia.
⁵ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁷ National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, W2 1PG, UK.
⁹ Department of Psychiatry, Washington University, St. Louis, MO, USA.
¹⁰ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
¹² Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
¹³ Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
¹⁴ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁵ Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK.
¹⁶ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹⁷ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508GA, Utrecht, The Netherlands.
²⁰ Center for Circulatory Health, University Medical Center Utrecht, 3508GA, Utrecht, The Netherlands.
²¹ Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
²² Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
²³ Department of Cardiology, Ealing Hospital, Middlesex, UB1 3HW, UK.
²⁴ Imperial College Healthcare NHS Trust, London, W12 0HS, UK.
²⁵ Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
²⁶ Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
²⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁸ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁹ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³⁰ Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³¹ Department of Medicine, Stanford University, Stanford, CA, USA.
³² Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³³ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.
³⁴ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge Centre, University of Cambridge, Cambridge, CB1 8RN, UK.
³⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
³⁷ MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK.
³⁸ National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust and Imperial College London, London, UK.
³⁹ UK Dementia Research Institute (UK DRI) at Imperial College London, London, UK.
⁴⁰ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁴¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁴² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475, Greifswald, Germany.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁴⁵ Department of Public Health and Clinical Medicine, Nutritional research, Umeå University, Umeå, Sweden.
⁴⁶ Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
⁴⁷ Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.
⁴⁸ University of Southern California, California, CA, USA.
⁴⁹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
⁵⁰ Centre for Genomic Health, Queen Mary University of London, London, EC1M 6BQ, UK.
⁵¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁵² Department of Public Health, University of Helsinki, Helsinki, Finland.
⁵³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁵⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
⁵⁵ Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, UK.
⁵⁶ Department of Public Health Solutions, National Institute for Health and Welfare, FI-00271, Helsinki, Finland.
⁵⁷ National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK.
⁵⁸ Department of Biostatistics, University of Washington School of Medicine, Seattle, WA, USA.
⁵⁹ University of Eastern Finland, Finland, Finland.
⁶⁰ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
⁶¹ Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
⁶² Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
⁶³ Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, H3T 1J4, Canada.
⁶⁴ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, SE1 9RT, UK.
⁶⁵ Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
⁶⁶ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁶⁷ Queensland Institute for Medical Research, Brisbane, Australia.
⁶⁸ Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683, Nicosia, Cyprus.
⁶⁹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
⁷⁰ Institute of Health Informatics, University College London, London, UK.
⁷¹ Department of Epidemiology and Public health, University Hospital of Strasbourg, Strasbourg, France.
⁷² Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷³ Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
⁷⁴ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
⁷⁵ Initiative for Noncommunicable Diseases, Health Systems and Population Studies Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
⁷⁶ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
⁷⁷ DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Greifswald, Germany.
⁷⁸ Department of Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 74, DK-2730, Herlev, Denmark.
⁷⁹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁸⁰ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy.
⁸¹ Department of Clinical Genetics, VU University Medical Centre Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
⁸² International Centre for Circulatory Health, Imperial College London, London, UK.
⁸³ Centre for Non-Communicable Diseases, Karachi, Pakistan.
⁸⁴ Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital, Lund University, SE-214 28, Malmö, Sweden.
⁸⁵ Department of Biobank Research, Umeå University, SE-901 87, Umeå, Sweden.
⁸⁶ Departments of Psychiatry and Mathematics, Washington University St. Louis, St. Louis, MO, USA.
⁸⁷ University of North Carolina, Chapel Hill, NC, USA.
⁸⁸ Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå universitet, SE, 90185, Umeå, Sweden.
⁸⁹ Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
⁹⁰ National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁹¹ Department of Psychology, University of Amsterdam & Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, Netherlands.
⁹² Alzheimer Scotland Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
⁹³ Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK.
⁹⁴ Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹⁵ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁹⁶ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
⁹⁷ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht University, 3508GA, Utrecht, The Netherlands.
⁹⁸ Department of gerontology and geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁹ Department of cardiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA, 02142, USA.
¹⁰¹ Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany.
¹⁰² Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰³ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰⁴ Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, 17475, Greifswald, Germany.
¹⁰⁵ Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.
¹⁰⁶ Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, PA, 16802, USA.
¹⁰⁷ Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA.
¹⁰⁸ Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, TX, USA.
¹⁰⁹ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UB1 3HW, UK.
¹¹⁰ Department of Biostatistics and Epidemiology, University of Pennsylvania, Pennsylvania, PA, USA.
¹¹¹ School of Medicine, University of Dundee, Dundee, UK.
¹¹² Department of Epidemiology and Public Health, Institut Pasteur de Lille, Lille, France.
¹¹³ Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
¹¹⁴ University Medical Center Hamburg Eppendorf, Hamburg, Germany.
¹¹⁵ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
¹¹⁶ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
¹¹⁷ EPIMED Research Centre, Department of Medicine and Surgery, University of Insubria at Varese, Varese, Italy.
¹¹⁸ Department of Epidemiology, UMR 1027- INSERM, Toulouse University-CHU Toulouse, Toulouse, France.
¹¹⁹ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
¹²⁰ Division of Respiratory Medicine and NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
¹²¹ Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, Umeå, Sweden.
¹²² Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
¹²³ The Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
¹²⁴ UKCRC Centre of Excellence for Public Health, Queens, University, Belfast, Belfast, UK.
¹²⁵ Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
¹²⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹²⁷ Population Health Research Institute, St George!s, University of London, London, SW17 0RE, UK.
¹²⁸ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹²⁹ Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, USA.
¹³⁰ Center for Non-Communicable Diseases, Karachi, Pakistan.
¹³¹ National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
¹³² Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA. dxl46@psu.edu.
¹³³ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. jmmh2@medschl.cam.ac.uk.

^# Contributed equally.

PMID: 30617275
PMCID: PMC7515840
DOI: 10.1038/s41380-018-0313-0

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 < 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.

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Conflict of interest statement

Paul W. Franks has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Neil Poulter has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents or both and consultancy fees. Peter Sever has received research awards from Pfizer. Mark J. Caulfield is Chief Scientist for Genomics England, a UK government company. Adam Butterworth reports grants from Merck and Pfizer and grants outside of this work from AstraZeneca, Biogen, and Novartis, and personal fees from Novartis. John Danesh reports grants, personal fees and non-financial support from Merck Sharp & Dohme (MSD), grants, personal fees and non-financial support from Novartis, grants from British Heart Foundation, grants from European Research Council, grants from NIHR, grants from NHS Blood and Transplant, grants from Pfizer, grants from UK MRC, grants from Wellcome Trust, grants from AstraZeneca, outside the submitted work. Laura J. Bierut is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction.

Figures

**Fig. 1**
Study design including the discovery and replication stages. NB: Gene-based studies, conditional analyses, and replication in African American ancestry samples not shown here for clarity. *GFG and NAGOZALC studies contributed additional custom content

**Fig. 2**
A concentric Circos plot of the association results for smoking initiation (SI; outer ring), cigarettes per day (CPD) and smoking cessation (SC; inner ring) for chromosomes 1–22 (Pack-years results, which can be found in Supp. Figure 1, are omitted for clarity). Each dot represents a SNV, with the X and Y axes corresponding to genomic location in Mb and -log₁₀P-values, respectively. Labels show the nearest gene to the novel sentinel variants identified in the discovery stage and taken forward to replication. The top signals were truncated at 10⁻¹⁰ for clarity. Novel and previously reported signals are highlighted in red and dark blue, respectively. Grey rings on the y-axis increase by increments of 2 (initial ring corresponding to P = 0.001, then 0.00001 etc.); and the outer and inner red rings correspond to the genome-wide significance level (P = 5 × 10⁻⁸) and P = 5 × 10⁻⁷, respectively. Image was created using Circos (v0.65)

See this image and copyright information in PMC

References

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

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

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