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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; Morris, RW; Fluharty, ME; Bjorngaard, JH; Åsvold, BO; Gabrielsen, ME; Campbell, A; Marioni, R; Kumari, M; Hällfors, J; et al. Taylor, AE; Morris, RW; Fluharty, ME; Bjorngaard, JH; Åsvold, 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 1553-7404 https://doi.org/10.1371/journal.pgen.1004799
SGUL Authors: Whincup, Peter Hynes

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Abstract

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
Additional Information: © 2014 Taylor et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Developmental Biology, 0604 Genetics
SGUL Research Institute / Research Centre: Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: PLoS Genetics
ISSN: 1553-7404
Language: eng
Dates:
DateEvent
4 December 2014Published
Projects:
Project IDFunderFunder ID
102215Wellcome TrustUNSPECIFIED
MC_UU_12013/1Medical Research CouncilUNSPECIFIED
MR/J01351X/1Medical Research CouncilUNSPECIFIED
PubMed ID: 25474695
Web of Science ID: WOS:000346649900013
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107348
Publisher's version: https://doi.org/10.1371/journal.pgen.1004799

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