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

Taylor, AE and Morris, RW and Fluharty, ME and Bjorngaard, JH and Åsvold, BO and Gabrielsen, ME and Campbell, A and Marioni, R and Kumari, M and Hällfors, J and Männistö, S and Marques-Vidal, P and Kaakinen, M and Cavadino, A and Postmus, I and Husemoen, LLN and Skaaby, T and Ahluwalia, TS and Treur, JL and Willemsen, G and Dale, C and Wannamethee, SG and Lahti, J and Palotie, A and Räikkönen, K and Kisialiou, A and McConnachie, A and Padmanabhan, S and Wong, A and Dalgård, C and Paternoster, L and Ben-Shlomo, Y and Tyrrell, J and Horwood, J and Fergusson, DM and Kennedy, MA and Frayling, T and Nohr, EA and Christiansen, L and Ohm Kyvik, K and Kuh, D and Watt, G and Eriksson, J and Whincup, PH and Vink, JM and Boomsma, DI and Davey Smith, G and Lawlor, D and Linneberg, A and Ford, I and Jukema, JW and Power, C and Hyppönen, E and Jarvelin, MR and Preisig, M and Borodulin, K and Kaprio, J and Kivimaki, M and Smith, BH and Hayward, C and Romundstad, PR and Sørensen, TIA and Munafò, MR (2014) 'Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers.' PLoS Genetics, 10 (12). ISSN 1553-7390

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Abstract

© 2014 Taylor et al. 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
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences > Institute for Social and Economic Research
Depositing User: Jim Jamieson
Date Deposited: 02 Feb 2015 17:02
Last Modified: 20 Mar 2019 01:15
URI: http://repository.essex.ac.uk/id/eprint/12538

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