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

Publication type

Journal Article


Publication date

December 15, 2014


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.

Published in

PLoS Genetics


Volume: 10






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.



Latest findings, new research

Publications search

Search all research by subject and author


Researchers discuss their findings and what they mean for society


Background and context, methods and data, aims and outputs


Conferences, seminars and workshops

Survey methodology

Specialist research, practice and study

Taking the long view

ISER's annual report


Key research themes and areas of interest