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; +54 more... 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 IA Sørensen; Marcus R Munafò; Naveed Sattar; (2014) Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers. PLoS genetics, 10 (12). e1004799-. ISSN 1553-7390 DOI: 10.1371/journal.pgen.1004799

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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.