PLoS Genetics (Dec 2014)

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

  • Amy E Taylor,
  • Richard W Morris,
  • Meg E Fluharty,
  • Johan H Bjorngaard,
  • 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,
  • Naveed Sattar

DOI
https://doi.org/10.1371/journal.pgen.1004799
Journal volume & issue
Vol. 10, no. 12
p. e1004799

Abstract

Read online

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.