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)

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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:McConnachie, Dr Alex and Davey Smith, Professor George and Ford, Professor Ian and Padmanabhan, Professor Sandosh and Watt, Professor Graham 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 > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Health and 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

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