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.
authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, United Kingdom; UK Centre for Tobacco and Alcohol Research Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
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authors.affiliation: MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, United Kingdom; UK Centre for Tobacco and Alcohol Research Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
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authors.affiliation: Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
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authors.affiliation: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; Institute of Health Sciences, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D055106:Genome-Wide Association Study; D005838:Genotype; D006304:Health Status; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012720:Severity of Illness Index; D012907:Smoking / Q000453:epidemiology / Q000235:genetics*; D015431:Weight Loss / Q000235:genetics; D055815:Young Adult
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human