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

Taylor, AE; Morris, RW; Fluharty, ME; Bjorngaard, JH; Asvold, BO; Gabrielsen, ME; Campbell, A; Marioni, R; Kumari, M; Hällfors, J; Männistö, S; Marques-Vidal, P; Kaakinen, M; Cavadino, A; Postmus, I; Husemoen, LL; Skaaby, T; Ahluwalia, TS; Treur, JL; Willemsen, G; Dale, C; Wannamethee, SG; Lahti, J; Palotie, A; Räikkönen, K; Kisialiou, A; McConnachie, A; Padmanabhan, S; Wong, A; Dalgård, C; Paternoster, L; Ben-Shlomo, Y; Tyrrell, J; Horwood, J; Fergusson, DM; Kennedy, MA; Frayling, T; Nohr, EA; Christiansen, L; Ohm Kyvik, K; Kuh, D; Watt, G; Eriksson, J; Whincup, PH; Vink, JM; Boomsma, DI; Davey Smith, G; Lawlor, D; Linneberg, A; Ford, I; Jukema, JW; Power, C; Hyppönen, E; Jarvelin, MR; Preisig, M; Borodulin, K; Kaprio, J; Kivimaki, M; Smith, BH; Hayward, C; Romundstad, PR; Sørensen, TI; Munafò, MR; Sattar, N; (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:

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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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
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PubMed ID: 25474695
Web of Science ID: 346649900013


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