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

Taylor, A. E. et al. (2014) Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers. PLoS Genetics, 10(12), e1004799. (doi: 10.1371/journal.pgen.1004799)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Davey Smith, Professor George and Watt, Professor Graham and McConnachie, Professor Alex and Ford, Professor Ian and Padmanabhan, Professor Sandosh and Sattar, Professor Naveed and Kisialiou, Dr Aliaksei
• Authors: Taylor, A. E., Morris, R. W., Fluharty, M. E., Bjorngaard, J. H., Åsvold, B. O., Gabrielsen, M. E., Campbell, A., Marioni, R., Kumari, M., Hällfors, J., Männistö, S., Marques-Vidal, P., Kaakinen, M., Cavadino, A., Postmus, I., Husemoen, L. L. N., Skaaby, T., Ahluwalia, T. S., Treur, J. L., Willemsen, G., Dale, C., Wannamethee, S. G., Lahti, J., Palotie, A., Räikkönen, K., Kisialiou, A., McConnachie, A., Padmanabhan, S., Wong, A., Dalgård, C., Paternoster, L., Ben-Shlomo, Y., Tyrrell, J., Horwood, J., Fergusson, D. M., Kennedy, M. A., Frayling, T., Nohr, E. A., Christiansen, L., Ohm Kyvik, K., Kuh, D., Watt, G., Eriksson, J., Whincup, P. H., Vink, J. M., Boomsma, D. I., Davey Smith, G., Lawlor, D., Linneberg, A., Ford, I., Jukema, J. W., Power, C., Hyppönen, E., Jarvelin, M.-R., Preisig, M., Borodulin, K., Kaprio, J., Kivimaki, M., Smith, B. H., Hayward, C., Romundstad, P. R., Sørensen, T. I.A., Munafò, M. R., and Sattar, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care
• Journal Name: PLoS Genetics
• Publisher: Public Library of Science
• ISSN: 1553-7404
• ISSN (Online): 1553-7404
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in PLoS Genetics 10(12):e1004799
• Publisher Policy: Reproduced under a Creative Commons License