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, Tellervo Korhonen, Jaakko Kaprio, Anu Loukola, Miina Ollikainen

Research output: Contribution to JournalArticleAcademicpeer-review

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.

LanguageEnglish
Article number1
Pages1-13
Number of pages13
JournalClinical epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - 5 Jan 2019

Fingerprint

Cotinine
Nicotine
DNA Methylation
Smoking
Serum
Methylation
Single Nucleotide Polymorphism
Genotype
Quantitative Trait Loci
Proxy
Epigenomics
Biomarkers
Health
Genes

Bibliographical note

06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1117 Public Health and Health Services

Keywords

  • Causal inference
  • Cotinine
  • Epigenome-wide association study
  • Genetic risk score
  • meQTL
  • Molecular mediation
  • Nicotine metabolism
  • Smoking

Cite this

Gupta, Richa ; Van Dongen, Jenny ; Fu, Yu ; Abdellaoui, Abdel ; Tyndale, Rachel F. ; Velagapudi, Vidya ; Boomsma, Dorret I. ; Korhonen, Tellervo ; Kaprio, Jaakko ; Loukola, Anu ; Ollikainen, Miina. / Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci. In: Clinical epigenetics. 2019 ; Vol. 11, No. 1. pp. 1-13.
@article{38a2dd1b475d4a2c9f630fd9c045541e,
title = "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.",
keywords = "Causal inference, Cotinine, Epigenome-wide association study, Genetic risk score, meQTL, Molecular mediation, Nicotine metabolism, Smoking",
author = "Richa Gupta and {Van Dongen}, Jenny and Yu Fu and Abdel Abdellaoui and Tyndale, {Rachel F.} and Vidya Velagapudi and Boomsma, {Dorret I.} and Tellervo Korhonen and Jaakko Kaprio and Anu Loukola and Miina Ollikainen",
note = "06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1117 Public Health and Health Services",
year = "2019",
month = "1",
day = "5",
doi = "10.1186/s13148-018-0606-9",
language = "English",
volume = "11",
pages = "1--13",
journal = "Clinical epigenetics",
issn = "1868-7083",
publisher = "Springer Verlag",
number = "1",

}

Gupta, R, Van Dongen, J, Fu, Y, Abdellaoui, A, Tyndale, RF, Velagapudi, V, Boomsma, DI, Korhonen, T, Kaprio, J, Loukola, A & Ollikainen, M 2019, 'Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci', Clinical epigenetics, vol. 11, no. 1, 1, pp. 1-13. https://doi.org/10.1186/s13148-018-0606-9

Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci. / Gupta, Richa; Van Dongen, Jenny; Fu, Yu; Abdellaoui, Abdel; Tyndale, Rachel F.; Velagapudi, Vidya; Boomsma, Dorret I.; Korhonen, Tellervo; Kaprio, Jaakko; Loukola, Anu; Ollikainen, Miina.

In: Clinical epigenetics, Vol. 11, No. 1, 1, 05.01.2019, p. 1-13.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Epigenome-wide association study of serum cotinine in current smokers reveals novel genetically driven loci

AU - Gupta, Richa

AU - Van Dongen, Jenny

AU - Fu, Yu

AU - Abdellaoui, Abdel

AU - Tyndale, Rachel F.

AU - Velagapudi, Vidya

AU - Boomsma, Dorret I.

AU - Korhonen, Tellervo

AU - Kaprio, Jaakko

AU - Loukola, Anu

AU - Ollikainen, Miina

N1 - 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1117 Public Health and Health Services

PY - 2019/1/5

Y1 - 2019/1/5

N2 - 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.

AB - 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.

KW - Causal inference

KW - Cotinine

KW - Epigenome-wide association study

KW - Genetic risk score

KW - meQTL

KW - Molecular mediation

KW - Nicotine metabolism

KW - Smoking

UR - http://www.scopus.com/inward/record.url?scp=85059500813&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059500813&partnerID=8YFLogxK

U2 - 10.1186/s13148-018-0606-9

DO - 10.1186/s13148-018-0606-9

M3 - Article

VL - 11

SP - 1

EP - 13

JO - Clinical epigenetics

T2 - Clinical epigenetics

JF - Clinical epigenetics

SN - 1868-7083

IS - 1

M1 - 1

ER -