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

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

doi:10.1371/journal.pgen.1004799

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

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

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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.

Original language	English
Journal	Plos Genetics
Volume	10
Issue number	12
Early online date	4 Dec 2014
DOIs	https://doi.org/10.1371/journal.pgen.1004799
Publication status	Published - 4 Dec 2014

Bibliographical note

Publisher Copyright:
© 2014 Taylor et al.

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Taylor, A. E., Morris, R. W., Fluharty, M. E., Bjorngaard, J. H., Åsvold, B. O., Gabrielsen, M. E., Campbell, A., Marioni, R., Kumari, M., Hällfors, J., Männistö, S., Marques-Vidal, P., Kaakinen, M., Cavadino, A., Postmus, I., Husemoen, L. L. N., Skaaby, T., Ahluwalia, T. S., Treur, J. L., ... 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). https://doi.org/10.1371/journal.pgen.1004799

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, LLN, 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, TIA, 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, vol. 10, no. 12. https://doi.org/10.1371/journal.pgen.1004799

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

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.",

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AU - Taylor, Amy E.

AU - Morris, Richard W.

AU - Fluharty, Meg E.

AU - Bjorngaard, Johan H.

AU - Åsvold, Bjørn Olav

AU - Gabrielsen, Maiken E.

AU - Campbell, Archie

AU - Marioni, Riccardo

AU - Kumari, Meena

AU - Hällfors, Jenni

AU - Männistö, Satu

AU - Marques-Vidal, Pedro

AU - Kaakinen, Marika

AU - Cavadino, Alana

AU - Postmus, Iris

AU - Husemoen, Lise Lotte N.

AU - Skaaby, Tea

AU - Ahluwalia, Tarunveer S.

AU - Treur, Jorien L.

AU - Willemsen, Gonneke

AU - Dale, Caroline

AU - Wannamethee, S. Goya

AU - Lahti, Jari

AU - Palotie, Aarno

AU - Räikkönen, Katri

AU - Kisialiou, Aliaksei

AU - McConnachie, Alex

AU - Padmanabhan, Sandosh

AU - Wong, Andrew

AU - Dalgård, Christine

AU - Paternoster, Lavinia

AU - Ben-Shlomo, Yoav

AU - Tyrrell, Jessica

AU - Horwood, John

AU - Fergusson, David M.

AU - Kennedy, Martin A.

AU - Frayling, Tim

AU - Nohr, Ellen A.

AU - Christiansen, Lene

AU - Ohm Kyvik, Kirsten

AU - Kuh, Diana

AU - Watt, Graham

AU - Eriksson, Johan

AU - Whincup, Peter H.

AU - Vink, Jacqueline M.

AU - Boomsma, Dorret I.

AU - Davey Smith, George

AU - Lawlor, Debbie

AU - Linneberg, Allan

AU - Ford, Ian

AU - Jukema, J. Wouter

AU - Power, Christine

AU - Hyppönen, Elina

AU - Jarvelin, Marjo Riitta

AU - Preisig, Martin

AU - Borodulin, Katja

AU - Kaprio, Jaakko

AU - Kivimaki, Mika

AU - Smith, Blair H.

AU - Hayward, Caroline

AU - Romundstad, Pål R.

AU - Sørensen, Thorkild I.A.

AU - Munafò, Marcus R.

AU - Sattar, Naveed

PY - 2014/12/4

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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