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; Tarun Veer Singh 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, Tarun Veer Singh 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

37 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
Journal	P L o S Genetics
Volume	10
Issue number	12
Pages (from-to)	1-6
Number of pages	6
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1004799
Publication status	Published - 1 Dec 2014

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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. V. 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. P L o S Genetics, 10(12), 1-6. [e1004799]. 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, TVS, 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, M-R, 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', P L o S Genetics, vol. 10, no. 12, e1004799, pp. 1-6. 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.",

author = "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, {Tarun Veer Singh} 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 Jukema, {J Wouter} and Christine Power and Elina Hypp{\"o}nen and Marjo-Riitta Jarvelin and Martin Preisig and Katja Borodulin and Jaakko Kaprio and Mika Kivimaki and Smith, {Blair H} and Caroline Hayward and Romundstad, {P{\aa}l R} and S{\o}rensen, {Thorkild I A} and Munaf{\`o}, {Marcus R} and Naveed Sattar",

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T1 - Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers

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, Tarun Veer Singh

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 - 2014/12/1

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.

U2 - 10.1371/journal.pgen.1004799

DO - 10.1371/journal.pgen.1004799

M3 - Journal article

C2 - 25474695

SN - 1553-7390

VL - 10

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EP - 6

JO - P L o S Genetics

JF - P L o S 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

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