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

Taylor, Amy E and Morris, Richard W and Fluharty, Meg E and Bjorngaard, Johan H and Åsvold, Bjørn Olav and Gabrielsen, Maiken E and Campbell, Archie and Marioni, Riccardo and Kumari, Meena and Hällfors, Jenni and Männistö, Satu and Marques-Vidal, Pedro and Kaakinen, Marika and Cavadino, Alana and Postmus, Iris and Husemoen, Lise Lotte N and Skaaby, Tea and Ahluwalia, Tarunveer S and Treur, Jorien L and Willemsen, Gonneke and Dale, Caroline and Wannamethee, S Goya and Lahti, Jari and Palotie, Aarno and Räikkönen, Katri and Kisialiou, Aliaksei and McConnachie, Alex and Padmanabhan, Sandosh and Wong, Andrew and Dalgård, Christine and Paternoster, Lavinia and Ben-Shlomo, Yoav and Tyrrell, Jessica and Horwood, John and Fergusson, David M and Kennedy, Martin A and Frayling, Tim and Nohr, Ellen A and Christiansen, Lene and Ohm Kyvik, Kirsten and Kuh, Diana and Watt, Graham and Eriksson, Johan and Whincup, Peter H and Vink, Jacqueline M and Boomsma, Dorret I and Davey Smith, George and Lawlor, Debbie and Linneberg, Allan and Ford, Ian and Jukema, J Wouter and Power, Christine and Hyppönen, Elina and Jarvelin, Marjo-Riitta and Preisig, Martin and Borodulin, Katja and Kaprio, Jaakko and Kivimaki, Mika and Smith, Blair H and Hayward, Caroline and Romundstad, Pål R and Sørensen, Thorkild IA and Munafò, Marcus R and Sattar, Naveed (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-e1004799. ISSN 1553-7390

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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
Uncontrolled Keywords: Humans; Weight Loss; Receptors, Nicotinic; Nerve Tissue Proteins; Body Mass Index; Severity of Illness Index; Smoking; Health Status; Genotype; Polymorphism, Single Nucleotide; Multigene Family; Adolescent; Adult; Aged; Aged, 80 and over; Middle Aged; Genome-Wide Association Study; Young Adult
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 02 Feb 2015 17:02
Last Modified: 15 Jan 2022 00:27
URI: http://repository.essex.ac.uk/id/eprint/12538

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