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

CARTA; B.O. Asvold; C. Dalgard; J.W. Jukema; C. Power; E. Hyppönen; M.R. Järvelin; M. Preisig; K. Borodulin; J. Kaprio; M. Kivimaki; B.H. Smith; C. Hayward; P.R. Romundstad; T.I.A. Sørensen; M.R. Munafo; N. Sattar

doi:https://doi.org/10.1371/journal.pgen.1004799

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

CARTA, B.O. Asvold, C. Dalgard, J.W. Jukema, C. Power, E. Hyppönen, M.R. Järvelin, M. Preisig, K. Borodulin, J. Kaprio, M. Kivimaki, B.H. Smith, C. Hayward, P.R. Romundstad, T.I.A. Sørensen, M.R. Munafo, N. Sattar

Research output: Contribution to journal › Article › Academic › peer-review

43 Citations (Scopus)

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
Article number	e1004799
Number of pages	6
Journal	PLoS genetics
Volume	10
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1004799
Publication status	Published - 1 Dec 2014

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

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

Access to Document

https://doi.org/10.1371/journal.pgen.1004799

http://www.tweelingenregister.org/publicaties

Cite this

CARTA, Asvold, B. O., Dalgard, C., Jukema, J. W., Power, C., Hyppönen, E., Järvelin, M. R., Preisig, M., Borodulin, K., Kaprio, J., Kivimaki, M., Smith, B. H., Hayward, C., Romundstad, P. R., Sørensen, T. I. A., Munafo, M. R., & 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), Article e1004799. https://doi.org/10.1371/journal.pgen.1004799

@article{a63f66be72e848a5adf7402eb594a267,

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.",

author = "CARTA and Taylor, {Amy E.} and Morris, {Richard W.} and Fluharty, {Meg E.} and Bjorngaard, {Johan H.} and {\AA}svold, {Bj{\o}rn Olav} and Gabrielsen, {Maiken E.} and Archie Campbell and Riccardo Marioni and Meena Kumari and Jenni H{\"a}llfors and Satu M{\"a}nnist{\"o} and Pedro Marques-Vidal and Marika Kaakinen and Alana Cavadino and Iris Postmus and Husemoen, {Lise Lotte N.} and Tea Skaaby and Ahluwalia, {Tarunveer S.} and Treur, {Jorien L.} and Gonneke Willemsen and Caroline Dale and Wannamethee, {S. Goya} and Jari Lahti and Aarno Palotie and Katri R{\"a}ikk{\"o}nen and Aliaksei Kisialiou and Alex McConnachie and Sandosh Padmanabhan and Andrew Wong and Christine Dalg{\aa}rd and Lavinia Paternoster and Yoav Ben-Shlomo and Jessica Tyrrell and John Horwood and Fergusson, {David M.} and Kennedy, {Martin A.} and Tim Frayling and Nohr, {Ellen A.} and Lene Christiansen and {Ohm Kyvik}, Kirsten and Diana Kuh and Graham Watt and Johan Eriksson and Whincup, {Peter H.} and Vink, {Jacqueline M.} and Boomsma, {Dorret I.} and {Davey Smith}, George and Debbie Lawlor and Allan Linneberg and Ian Ford and B.O. Asvold and C. Dalgard and J.W. Jukema and C. Power and E. Hypp{\"o}nen and M.R. J{\"a}rvelin and M. Preisig and K. Borodulin and J. Kaprio and M. Kivimaki and B.H. Smith and C. Hayward and P.R. Romundstad and T.I.A. S{\o}rensen and M.R. Munafo and N. Sattar",

note = "Publisher Copyright: {\textcopyright} 2014 Taylor et al.",

year = "2014",

month = dec,

day = "1",

doi = "https://doi.org/10.1371/journal.pgen.1004799",

language = "English",

volume = "10",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "12",

}

CARTA, Asvold, BO, Dalgard, C, Jukema, JW, Power, C, Hyppönen, E, Järvelin, MR, Preisig, M, Borodulin, K, Kaprio, J, Kivimaki, M, Smith, BH, Hayward, C, Romundstad, PR, Sørensen, TIA, Munafo, 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, e1004799. https://doi.org/10.1371/journal.pgen.1004799

TY - JOUR

T1 - Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers

AU - CARTA

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 - Asvold, B.O.

AU - Dalgard, C.

AU - Jukema, J.W.

AU - Power, C.

AU - Hyppönen, E.

AU - Järvelin, M.R.

AU - Preisig, M.

AU - Borodulin, K.

AU - Kaprio, J.

AU - Kivimaki, M.

AU - Smith, B.H.

AU - Hayward, C.

AU - Romundstad, P.R.

AU - Sørensen, T.I.A.

AU - Munafo, M.R.

AU - Sattar, N.

PY - 2014/12/1

Y1 - 2014/12/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84919663860&partnerID=8YFLogxK

U2 - https://doi.org/10.1371/journal.pgen.1004799

DO - https://doi.org/10.1371/journal.pgen.1004799

M3 - Article

C2 - 25474695

SN - 1553-7390

VL - 10

JO - PLoS genetics

JF - PLoS genetics

IS - 12

M1 - e1004799

ER -

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

Abstract

Cohort Studies

UN SDGs

Access to Document

Other files and links

Cite this