Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

D. B. Hancock, Y. Guo, G. W. Reginsson, N. C. Gaddis, S. M. Lutz, R. Sherva, A. Loukola, C. C. Minica, C. A. Markunas, Y. Han, K. A. Young, D. F. Gudbjartsson, F. Gu, D. W. McNeil, B. Qaiser, C. Glasheen, S. Olson, M. T. Landi, P. A.F. Madden, L. A. Farrer & 18 others J. Vink, N. L. Saccone, M. C. Neale, H. R. Kranzler, J. McKay, R. J. Hung, C. I. Amos, M. L. Marazita, D. I. Boomsma, T. B. Baker, J. Gelernter, J. Kaprio, N. E. Caporaso, T. E. Thorgeirsson, J. E. Hokanson, L. J. Bierut, K. Stefansson, E. O. Johnson

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77%) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10−4, OR=1.05, and 95% CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10−26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10−6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

LanguageEnglish
Pages1-9
Number of pages9
JournalMolecular Psychiatry
Volume23
Issue number9
DOIs
Publication statusPublished - 3 Oct 2018

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Tobacco Use Disorder
Genome-Wide Association Study
African Americans
Single Nucleotide Polymorphism
Smoking
Meta-Analysis
Quantitative Trait Loci
Odds Ratio
Confidence Intervals
Methylation
Lung Neoplasms
Brain
Almanacs
Genes
Phenotype
Methyltransferases
Proxy
Cholinergic Receptors
Nicotine
Gene Frequency

Keywords

  • Journal Article

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Hancock, D. B. ; Guo, Y. ; Reginsson, G. W. ; Gaddis, N. C. ; Lutz, S. M. ; Sherva, R. ; Loukola, A. ; Minica, C. C. ; Markunas, C. A. ; Han, Y. ; Young, K. A. ; Gudbjartsson, D. F. ; Gu, F. ; McNeil, D. W. ; Qaiser, B. ; Glasheen, C. ; Olson, S. ; Landi, M. T. ; Madden, P. A.F. ; Farrer, L. A. ; Vink, J. ; Saccone, N. L. ; Neale, M. C. ; Kranzler, H. R. ; McKay, J. ; Hung, R. J. ; Amos, C. I. ; Marazita, M. L. ; Boomsma, D. I. ; Baker, T. B. ; Gelernter, J. ; Kaprio, J. ; Caporaso, N. E. ; Thorgeirsson, T. E. ; Hokanson, J. E. ; Bierut, L. J. ; Stefansson, K. ; Johnson, E. O. / Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 9. pp. 1-9.
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abstract = "Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77{\%}) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95{\%} confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10−4, OR=1.05, and 95{\%} CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95{\%} CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10−26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10−6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.",
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Hancock, DB, Guo, Y, Reginsson, GW, Gaddis, NC, Lutz, SM, Sherva, R, Loukola, A, Minica, CC, Markunas, CA, Han, Y, Young, KA, Gudbjartsson, DF, Gu, F, McNeil, DW, Qaiser, B, Glasheen, C, Olson, S, Landi, MT, Madden, PAF, Farrer, LA, Vink, J, Saccone, NL, Neale, MC, Kranzler, HR, McKay, J, Hung, RJ, Amos, CI, Marazita, ML, Boomsma, DI, Baker, TB, Gelernter, J, Kaprio, J, Caporaso, NE, Thorgeirsson, TE, Hokanson, JE, Bierut, LJ, Stefansson, K & Johnson, EO 2018, 'Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence', Molecular Psychiatry, vol. 23, no. 9, pp. 1-9. https://doi.org/10.1038/mp.2017.193

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. / Hancock, D. B.; Guo, Y.; Reginsson, G. W.; Gaddis, N. C.; Lutz, S. M.; Sherva, R.; Loukola, A.; Minica, C. C.; Markunas, C. A.; Han, Y.; Young, K. A.; Gudbjartsson, D. F.; Gu, F.; McNeil, D. W.; Qaiser, B.; Glasheen, C.; Olson, S.; Landi, M. T.; Madden, P. A.F.; Farrer, L. A.; Vink, J.; Saccone, N. L.; Neale, M. C.; Kranzler, H. R.; McKay, J.; Hung, R. J.; Amos, C. I.; Marazita, M. L.; Boomsma, D. I.; Baker, T. B.; Gelernter, J.; Kaprio, J.; Caporaso, N. E.; Thorgeirsson, T. E.; Hokanson, J. E.; Bierut, L. J.; Stefansson, K.; Johnson, E. O.

In: Molecular Psychiatry, Vol. 23, No. 9, 03.10.2018, p. 1-9.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

AU - Hancock, D. B.

AU - Guo, Y.

AU - Reginsson, G. W.

AU - Gaddis, N. C.

AU - Lutz, S. M.

AU - Sherva, R.

AU - Loukola, A.

AU - Minica, C. C.

AU - Markunas, C. A.

AU - Han, Y.

AU - Young, K. A.

AU - Gudbjartsson, D. F.

AU - Gu, F.

AU - McNeil, D. W.

AU - Qaiser, B.

AU - Glasheen, C.

AU - Olson, S.

AU - Landi, M. T.

AU - Madden, P. A.F.

AU - Farrer, L. A.

AU - Vink, J.

AU - Saccone, N. L.

AU - Neale, M. C.

AU - Kranzler, H. R.

AU - McKay, J.

AU - Hung, R. J.

AU - Amos, C. I.

AU - Marazita, M. L.

AU - Boomsma, D. I.

AU - Baker, T. B.

AU - Gelernter, J.

AU - Kaprio, J.

AU - Caporaso, N. E.

AU - Thorgeirsson, T. E.

AU - Hokanson, J. E.

AU - Bierut, L. J.

AU - Stefansson, K.

AU - Johnson, E. O.

PY - 2018/10/3

Y1 - 2018/10/3

N2 - Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77%) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10−4, OR=1.05, and 95% CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10−26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10−6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

AB - Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44–77%) was associated with increased risk of nicotine dependence at P=3.7 × 10−8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04–1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10−4, OR=1.05, and 95% CI=1.02–1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01–1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10−26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10−6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

KW - Journal Article

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U2 - 10.1038/mp.2017.193

DO - 10.1038/mp.2017.193

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