Journal Article

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with Body Mass Index in never smokers

By Amy E. Taylor, Richard W. Morris, Meg E. Fluharty, Johan H. Bjørngaard, Bjørn Olav Åsvold, Maiken E. Gabrielsen, Archie Campbell, Riccardo Marioni, Meena Kumari, Jenni Hällfors, Satu Männistö, Pedro Marques-Vidal, Marika Kaakinen, Alana Cavadino, Iris Postmus, Lise Lotte N. Husemoen, Tea Skaaby, Tarunveer S. Ahluwalia, Jorien L. Treur, Gonneke Willemsen, Caroline Dale, S. Goya Wannamethee, Jari Lahti, Aarno Palotie, Katri Räikkönen, Aliaksei Kisialiou, Alex McConnachie, Sandosh Padmanabhan, Andrew Wong, Christine Dalgård, Lavinia Paternoster, Yoav Ben-Shlomo, Jessica Tyrrell, John Horwood, David M. Fergusson, Martin A. Kennedy, Tim Frayling, Ellen A. Nohr, Lene Christiansen, Kirsten Ohm Kyvik, Diana Kuh, Graham Watt, Johan Eriksson, Peter H. Whincup, Jacqueline M. Vink, Dorret I. Boomsma, George Davey Smith, Debbie Lawlor, Allan Linneberg, Ian Ford, J. Wouter Jukema, Christine Power, Elina Hyppönen, Marjo-Riitta Jarvelin, Martin Preisig, Katja Borodulin, Jaakko Kaprio, Mika Kivimaki, Blair H. Smith, Caroline Hayward, Pål R. Romundstad, Thorkild I. A. Sørensen, Marcus R. Munafò and Naveed Sattar

Publication details

Publication date
Published in
PLoS Genetics
Volume
10
Publisher
Public Library of Science
DOI
http://dx.doi.org/10.1371/journal.pgen.1004799
ISSN
15537390

Summary

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 = 2.00610210), but also unexpectedly found that it was associated
with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.3861025).
An interaction test confirmed that these estimates differed from each other (P
= 4.95610213). 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.

Notes

OpenAccess article

Copyright: © 2014 Taylor et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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