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

Title: Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers
Author(s): Taylor, AE
Morris, RW
Fluharty, ME
Bjorngaard, JH
Asvold, BO
Gabrielsen, ME
Campbell, A
Marioni, R
Kumari, M
Hallfors, J
Mannisto, 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
Raikkonen, K
Kisialiou, A
McConnachie, A
Padmanabhan, S
Wong, A
Dalgard, C
Paternoster, L
Ben-Shlomo, Y
Tyrrell, J
Horwood, J
Fergusson, DM
Kennedy, MA
Frayling, T
Nohr, EA
Christiansen, L
Kyvik, KO
Kuh, D
Watt, G
Eriksson, J
Whincup, PH
Vink, JM
Boomsma, DI
Smith, GD
Lawlor, D
Linneberg, A
Ford, I
Jukema, JW
Power, C
Hypponen, E
Jarvelin, M-R
Preisig, M
Borodulin, K
Kaprio, J
Kivimaki, M
Smith, BH
Hayward, C
Romundstad, PR
Sorensen, TIA
Munafo, MR
Sattar, N
Item Type: Journal Article
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.
Publication Date: 4-Dec-2014
Date of Acceptance: 2-Oct-2014
URI: http://hdl.handle.net/10044/1/48218
DOI: https://dx.doi.org/10.1371/journal.pgen.1004799
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLOS Genetics
Volume: 10
Issue: 12
Copyright Statement: © 2014 Taylor et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
NICOTINE DEPENDENCE
GENE
VARIANTS
BEHAVIOR
CLUSTER
DISEASE
LOCUS
LEVEL
Adolescent
Adult
Aged
Aged, 80 and over
Body Mass Index
Genome-Wide Association Study
Genotype
Health Status
Humans
Middle Aged
Multigene Family
Nerve Tissue Proteins
Polymorphism, Single Nucleotide
Receptors, Nicotinic
Severity of Illness Index
Smoking
Weight Loss
Young Adult
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
Developmental Biology
0604 Genetics
Publication Status: Published
Article Number: ARTN e1004799
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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