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

Authors: Gupta, Richa; van Dongen, Jenny; Fu, Yu; Abdellaoui, Abdel; Tyndale, Rachel F.; Velagapudi, Vidya; Boomsma, Dorret I.; +4 Authors

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

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.

Countries
Netherlands, Finland
Subjects by Vocabulary

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

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

Keywords

BIOMARKER, Epigenomics, Male, Netherlands Twin Register (NTR), BLOOD, ACCURACY, PATHWAY, Cytochrome P-450 CYP2A6, Cotinine, Genetics (clinical), Smoking, Middle Aged, Genetic risk score, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Female, CIGARETTE SMOKERS, Adult, Genotype, 3122 Cancers, Polymorphism, Single Nucleotide, Nicotine metabolism, Young Adult, SDG 3 - Good Health and Well-being, Epigenome-wide association study, SELF-REPORTED SMOKING, meQTL, /dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_, Genetics, Humans, Molecular Biology, Genetic Association Studies, Aged, Research, DIFFERENTIAL DNA METHYLATION, NICOTINE METABOLITE RATIO, DNA Methylation, Molecular mediation, CpG Islands, CESSATION, 3111 Biomedicine, LUNG, Causal inference, Developmental Biology

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    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 1%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
48
Top 1%
Average
Top 1%
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AKA| Epigenetic pathways to obesity
Project
  • Funder: Academy of Finland (AKA)
  • Project Code: 297908
,
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
,
NWO| BBMRI-NL
Project
  • Funder: Netherlands Organisation for Scientific Research (NWO) (NWO)
  • Project Code: 184.021.007
iis
,
AKA| Genomic epidemiology of addictions and their consequences - national, Nordic and international dimensions
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