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.