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PLoS Genet. 2014 Dec 4;10(12):e1004799. doi: 10.1371/journal.pgen.1004799. eCollection 2014 Dec.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

Author information

1
MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, United Kingdom; UK Centre for Tobacco and Alcohol Research Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
2
Department of Primary Care and Population Health, UCL, London, United Kingdom.
3
Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
4
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
5
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
6
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom; Queensland Brain Institute, University of Queensland, Brisbane, Australia.
7
Department of Epidemiology and Public Health, University College London, London, United Kingdom; Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom.
8
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
9
National Institute for Health and Welfare, Helsinki, Finland.
10
Department of Internal Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
11
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
12
Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom.
13
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands; Netherlands Consortium of Healthy Ageing, Leiden, The Netherlands.
14
Research Centre for Prevention and Health, The Capital Region, Copenhagen, Denmark.
15
Novo Nordisk Foundation Centre for Basic Metabolic Research, Metabolic Genetics Section, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.
16
Netherlands Twin Register, Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
17
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
18
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland.
19
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; The Medical and Population Genomics Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
20
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
21
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
22
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
23
MRC Unit for Lifelong Health and Ageing at UCL, London, United Kingdom.
24
Institute of Public Health, Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.
25
MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
26
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
27
European Centre for Environment and Human Health, University of Exeter Medical School, Truro, United Kingdom; Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
28
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
29
Department of Pathology, University of Otago, Christchurch, New Zealand.
30
Genetics of Complex Traits, University of Exeter Medical School, Exeter, United Kingdom.
31
Institute for Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Public Health, Aarhus University, Aarhus, Denmark.
32
Institute of Public Health, Dept. of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Denmark.
33
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.
34
Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.
35
National Institute for Health and Welfare, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; Vasa Central Hospital, Vasa, Finland.
36
Population Health Research Institute, St George's University of London, London, United Kingdom.
37
MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, United Kingdom; Institute of Public Health, Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.
38
Research Centre for Prevention and Health, The Capital Region, Copenhagen, Denmark; Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
39
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
40
Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom; School of Population Health and Sansom Institute, University of South Australia, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
41
Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Unit of Primary Care, Oulu University Hospital, Oulu, Finland; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
42
Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
43
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.
44
Department of Epidemiology and Public Health, University College London, London, United Kingdom.
45
University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
46
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
47
Novo Nordisk Foundation Centre for Basic Metabolic Research, Metabolic Genetics Section, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute of Preventive Medicine, Bispebrjerg and Frederikberg Hospitals, The Capital Region, Copenhagen, Denmark.
48
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.

Abstract

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

PMID:
25474695
PMCID:
PMC4256159
DOI:
10.1371/journal.pgen.1004799
[Indexed for MEDLINE]
Free PMC Article

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