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