Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers
Taylor, Amy E; Morris, Richard W; Fluharty, Meg; Bjørngaard, Johan Håkon; Åsvold, Bjørn Olav; Gabrielsen, Maiken Elvestad; Campbell, A.; Marioni, Riccardo R.; Kumari, Meena; Hällfors, Jenni; Männistö, Satu; Marques-Vidal, Pedro; Kaakinen, Marika; Cavadino, Alana; Postmus, Iris; Husemoen, Lise Lotte N; Skaaby, Tea; Ahluwalia, Tarunveer Singh; Treur, Jorien L; Willemsen, Gonneke; Dale, Caroline; Wannamethee, SG; Lahti, J; Palotie, Aarno; Räikkönen, K; Kisialiou, Aliaksei; McConnachie, Alex; Padmanabhan, Sandosh; Wong, Andrew; Dalgård, Christine; Paternoster, Lavinia; Ben-Shlomo, Yoav; Tyrrell, Jessica; Horwood, John; Fergusson, D; Kennedy, Martin A; Frayling, T; Nohr, Ellen A; Christiansen, Lene; Ohm Kyvik, K; Kuh, Diana; Watt, Graham; Eriksson, Johan; Whincup, Peter H; Vink, JM; Boomsma, Dorret I; Davey Smith, George; Lawlor, Debbie A; Linneberg, Allan; Ford, Ian; Jukema, J Wouter; Power, C; Hyppönen, E; Jarvelin, Marjo-Riitta; Preisig, Martin; Borodulin, Katja; Kaprio, Jaakko; Kivimaki, Mika; Smith, BH; Hayward, Caroline; Romundstad, Pål Richard; Sørensen, Thorkild I.A.; Munafo, Marcus R; Sattar, Naveed
Journal article, Peer reviewed
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Original versionPLoS Genetics. 2014, 10 (12) 10.1371/journal.pgen.1004799
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.