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Mol Psychiatry. 2019 Jan 7. doi: 10.1038/s41380-018-0313-0. [Epub ahead of print]

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

Erzurumluoglu AM1, Liu M2, Jackson VE1,3,4, Barnes DR5, Datta G2,6, Melbourne CA1, Young R5, Batini C1, Surendran P5, Jiang T5, Adnan SD7, Afaq S8, Agrawal A9, Altmaier E10, Antoniou AC11, Asselbergs FW12,13,14,15, Baumbach C10, Bierut L16, Bertelsen S17, Boehnke M18, Bots ML19,20, Brazel DM6,21, Chambers JC8,22,23,24, Chang-Claude J25,26, Chen C27,28, Corley J29,30, Chou YL9, David SP31, de Boer RA32, de Leeuw CA33, Dennis JG11, Dominiczak AF34, Dunning AM35, Easton DF11,35, Eaton C28, Elliott P36,37,38,39, Evangelou E8,40, Faul JD41, Foroud T42, Goate A17, Gong J27, Grabe HJ43, Haessler J27, Haiman C44, Hallmans G45, Hammerschlag AR33, Harris SE29,46, Hattersley A47, Heath A9, Hsu C48, Iacono WG2, Kanoni S49,50, Kapoor M17, Kaprio J51,52, Kardia SL53, Karpe F54,55, Kontto J56, Kooner JS23,24,37,57, Kooperberg C27,58, Kuulasmaa K56, Laakso M59, Lai D42, Langenberg C60, Le N61, Lettre G62,63, Loukola A51,52, Luan J60, Madden PAF9, Mangino M64,65, Marioni RE29,46, Marouli E49,50, Marten J66, Martin NG67, McGue M2, Michailidou K11,68, Mihailov E69, Moayyeri A70, Moitry M71, Müller-Nurasyid M72,73,74, Naheed A75, Nauck M76,77, Neville MJ54,55, Nielsen SF78, North K79, Perola M51,56, Pharoah PDP11,35, Pistis G80, Polderman TJ33, Posthuma D33,81, Poulter N82, Qaiser B51,52, Rasheed A83, Reiner A28,27, Renström F84,85, Rice J86, Rohde R87, Rolandsson O88, Samani NJ89, Samuel M83, Schlessinger D90, Scholte SH91, Scott RA60, Sever P57,82, Shao Y87, Shrine N1, Smith JA53, Starr JM29,92, Stirrups K49,93, Stram D94, Stringham HM18, Tachmazidou I95, Tardif JC62,63, Thompson DJ11, Tindle HA96, Tragante V97, Trompet S98,99, Turcot V62, Tyrrell J47, Vaartjes I19,20, van der Leij AR91, van der Meer P32, Varga TV84, Verweij N32,100, Völzke H77,101, Wareham NJ60, Warren HR102,103, Weir DR41, Weiss S77,104, Wetherill L42, Yaghootkar H47, Yavas E105,106, Jiang Y107, Chen F107, Zhan X108, Zhang W8,109, Zhao W110, Zhao W53, Zhou K111, Amouyel P112, Blankenberg S113,114, Caulfield MJ102,103, Chowdhury R5, Cucca F80, Deary IJ29,30, Deloukas P95,49,115, Di Angelantonio E5,116, Ferrario M117, Ferrières J118, Franks PW84,119, Frayling TM47, Frossard P83, Hall IP120, Hayward C66, Jansson JH121, Jukema JW122,123, Kee F124, Männistö S56, Metspalu A69, Munroe PB102,103, Nordestgaard BG78, Palmer CNA125, Salomaa V56, Sattar N126, Spector T65, Strachan DP127; Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium, van der Harst P32,128, Zeggini E95, Saleheen D5,129,130, Butterworth AS5,116, Wain LV1,131, Abecasis GR18, Danesh J5,95,116, Tobin MD1,131, Vrieze S2, Liu DJ132, Howson JMM133.

Author information

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.

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.

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

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