Article
Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers
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- (1) University of Bristol, grid.5337.2
- (2) University College London, grid.83440.3b
- (3) Norwegian University of Science and Technology, grid.5947.f
- (4) University of Edinburgh, grid.4305.2
- (5) University of Queensland, grid.1003.2
- (6) University of Essex, grid.8356.8
- (7) University of Helsinki, grid.7737.4
- (8) National Institute for Health and Welfare, grid.14758.3f
- (9) University Hospital of Lausanne, grid.8515.9
- (10) Imperial College London, grid.7445.2
- (11) University of Oulu, grid.10858.34
- (12) Netherlands Consortium for Healthy Ageing, grid.452197.c
- (13) Leiden University Medical Center, grid.10419.3d
- (14) Research Centre for Prevention and Health, grid.415878.7, Capital Region
- (15) Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
- (16) University of Copenhagen, grid.5254.6, KU
- (17) VU Amsterdam, grid.12380.38
- (18) London School of Hygiene & Tropical Medicine, grid.8991.9
- (19) Folkhälsans Forskningscentrum, grid.428673.c
- (20) Broad Institute, grid.66859.34
- (21) Wellcome Sanger Institute, grid.10306.34
- (22) University of Glasgow, grid.8756.c
- (23) MRC Unit for Lifelong Health and Ageing, grid.268922.5
- (24) University of Southern Denmark, grid.10825.3e, SDU
- (25) University of Exeter, grid.8391.3
- (26) University of Otago, grid.29980.3a
- (27) Aarhus University, grid.7048.b, AU
- (28) Odense University Hospital, grid.7143.1, Southern Denmark Region
- (29) Helsinki University Central Hospital, grid.15485.3d
- (30) Vaasa Central Hospital, grid.417201.1
- (31) St George's, University of London, grid.264200.2
- (32) Rigshospitalet, grid.475435.4, Capital Region
- (33) Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
- (34) Netherlands Heart Institute, grid.411737.7
- (35) South Australian Health and Medical Research Institute, grid.430453.5
- (36) University of South Australia, grid.1026.5
- (37) Oulu University Hospital, grid.412326.0
- (38) University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
- (39) Copenhagen University Hospital, grid.4973.9, Capital Region
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Description
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.