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Publication . Article . 2019

Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci

Richa Gupta; Jenny van Dongen; Yu Fu; Abdel Abdellaoui; Rachel F. Tyndale; Vidya Velagapudi; Dorret I. Boomsma; +4 Authors
Open Access
English
Abstract

Background DNA methylation alteration extensively associates with smoking and is a plausible link between smoking and adverse health. We examined the association between epigenome-wide DNA methylation and serum cotinine levels as a proxy of nicotine exposure and smoking quantity, assessed the role of SNPs in these associations, and evaluated molecular mediation by methylation in a sample of biochemically verified current smokers (N = 310). Results DNA methylation at 50 CpG sites was associated (FDR < 0.05) with cotinine levels, 17 of which are novel associations. As cotinine levels are influenced not only by nicotine intake but also by CYP2A6-mediated nicotine metabolism rate, we performed secondary analyses adjusting for genetic risk score of nicotine metabolism rate and identified five additional novel associations. We further assessed the potential role of genetic variants in the detected association between methylation and cotinine levels observing 124 cis and 3898 trans methylation quantitative trait loci (meQTLs). Nineteen of these SNPs were also associated with cotinine levels (FDR < 0.05). Further, at seven CpG sites, we observed a trend (P < 0.05) that altered DNA methylation mediates the effect of SNPs on nicotine exposure rather than a direct consequence of smoking. Finally, we performed replication of our findings in two independent cohorts of biochemically verified smokers (N = 450 and N = 79). Conclusions Using cotinine, a biomarker of nicotine exposure, we replicated and extended identification of novel epigenetic associations in smoking-related genes. We also demonstrated that DNA methylation in some of the identified loci is driven by the underlying genotype and may mediate the causal effect of genotype on cotinine levels. Electronic supplementary material The online version of this article (10.1186/s13148-018-0606-9) contains supplementary material, which is available to authorized users.

Subjects by Vocabulary

Library of Congress Subject Headings: lcsh:Medicine lcsh:R lcsh:Genetics lcsh:QH426-470

Microsoft Academic Graph classification: Single-nucleotide polymorphism CpG site Endocrinology medicine.medical_specialty medicine Genotype DNA methylation Cotinine chemistry.chemical_compound chemistry Internal medicine Epigenetics Methylation Nicotine medicine.drug Biology

Subjects

Epigenome-wide association study, Smoking, Cotinine, Genetic risk score, Nicotine metabolism, meQTL, Causal inference, Molecular mediation, NICOTINE METABOLITE RATIO, DIFFERENTIAL DNA METHYLATION, SELF-REPORTED SMOKING, CIGARETTE SMOKERS, BLOOD, BIOMARKER, PATHWAY, LUNG, CESSATION, ACCURACY, 3122 Cancers, 3111 Biomedicine, Netherlands Twin Register (NTR), SDG 3 - Good Health and Well-being, Genetics (clinical), Developmental Biology, Genetics, Molecular Biology, Research, Causal inference, Cotinine, Epigenome-wide association study, Genetic risk score, meQTL, Molecular mediation, Nicotine metabolism, Smoking, /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_, Netherlands Twin Register (NTR), /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, SDG 3 - Good Health and Well-being

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Funded byView all
AKA| CoE in Complex Disease Genetics
Project
  • Funder: Academy of Finland (AKA)
  • Project Code: 213506
,
NWO| BBMRI-NL
Project
  • Funder: Netherlands Organisation for Scientific Research (NWO) (NWO)
  • Project Code: 2300154272
,
AKA| Epigenetic pathways to obesity
Project
  • Funder: Academy of Finland (AKA)
  • Project Code: 297908
,
AKA| Center of Excellence in Complex Disease Genetics
Project
  • Funder: Academy of Finland (AKA)
  • Project Code: 129680
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Clinical Epigenetics
Article . 2019
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