Article open access publication

Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers

PLOS Genetics, Public Library of Science (PLoS), ISSN 1553-7390

Volume 10, 12, 2014

DOI:10.1371/journal.pgen.1004799, Dimensions: pub.1051161289, PMC: PMC4256159, PMID: 25474695,

Authors

Kumari, Meena (2) (6)
Kaakinen, Marika (10) (11)
Postmus, Iris (12) (13)
Lahti, Jari (7) (19)
Palotie, Aarno (7) (20) (21)
Nohr, Ellen A. (24) (27)
Kyvik, Kirsten Ohm (24) (28)
Kuh, Diana (23)
Eriksson, Johan (7) (8) (19) (29) (30)
Lawlor, Debbie (1) (24)
Linneberg, Allan (14) (16) (32)
Ford, Ian (22)
Jukema, J. Wouter (13) (33) (34)
Hyppönen, Elina (2) (35) (36)
Jarvelin, Marjo-Riitta (8) (10) (11) (37)
Kaprio, Jaakko (7) (8)

Affiliations

Organisations

  1. (1) University of Bristol, grid.5337.2
  2. (2) University College London, grid.83440.3b
  3. (3) Norwegian University of Science and Technology, grid.5947.f
  4. (4) University of Edinburgh, grid.4305.2
  5. (5) University of Queensland, grid.1003.2
  6. (6) University of Essex, grid.8356.8
  7. (7) University of Helsinki, grid.7737.4
  8. (8) National Institute for Health and Welfare, grid.14758.3f
  9. (9) University Hospital of Lausanne, grid.8515.9
  10. (10) Imperial College London, grid.7445.2
  11. (11) University of Oulu, grid.10858.34
  12. (12) Netherlands Consortium for Healthy Ageing, grid.452197.c
  13. (13) Leiden University Medical Center, grid.10419.3d
  14. (14) Research Centre for Prevention and Health, grid.415878.7, Capital Region
  15. (15) Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
  16. (16) University of Copenhagen, grid.5254.6, KU
  17. (17) VU Amsterdam, grid.12380.38
  18. (18) London School of Hygiene & Tropical Medicine, grid.8991.9
  19. (19) Folkhälsans Forskningscentrum, grid.428673.c
  20. (20) Broad Institute, grid.66859.34
  21. (21) Wellcome Sanger Institute, grid.10306.34
  22. (22) University of Glasgow, grid.8756.c
  23. (23) MRC Unit for Lifelong Health and Ageing, grid.268922.5
  24. (24) University of Southern Denmark, grid.10825.3e, SDU
  25. (25) University of Exeter, grid.8391.3
  26. (26) University of Otago, grid.29980.3a
  27. (27) Aarhus University, grid.7048.b, AU
  28. (28) Odense University Hospital, grid.7143.1, Southern Denmark Region
  29. (29) Helsinki University Central Hospital, grid.15485.3d
  30. (30) Vaasa Central Hospital, grid.417201.1
  31. (31) St George's, University of London, grid.264200.2
  32. (32) Rigshospitalet, grid.475435.4, Capital Region
  33. (33) Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  34. (34) Netherlands Heart Institute, grid.411737.7
  35. (35) South Australian Health and Medical Research Institute, grid.430453.5
  36. (36) University of South Australia, grid.1026.5
  37. (37) Oulu University Hospital, grid.412326.0
  38. (38) University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
  39. (39) Copenhagen University Hospital, grid.4973.9, Capital Region

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.

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NORA University Profiles

University of Copenhagen

University of Southern Denmark

Aarhus University

Dimensions Citation Indicators

Times Cited: 38

Field Citation Ratio (FCR): 4.33

Relative Citation ratio (RCR): 1.52

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