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Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers

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  • Amy E Taylor
  • Richard W Morris
  • Meg E Fluharty
  • Johan H Bjorngaard
  • Bjørn Olav Asvold
  • Maiken E Gabrielsen
  • 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
  • Pål R Romundstad
  • Thorkild I A Sørensen
  • Marcus R Munafò
  • Naveed Sattar

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    Rights statement: 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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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Article numbere1004799
JournalPLoS Genetics
Issue number12
Publication statusPublished - 4 Dec 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 = 2.00×10-10), 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.

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