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; 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

doi:10.1038/mp.2017.193

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. FarrerJ. 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

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	1911–1919
Number of pages	9
Journal	Molecular Psychiatry
Volume	23
Issue number	9
Early online date	3 Oct 2017
DOIs	https://doi.org/10.1038/mp.2017.193
Publication status	Published - Sept 2018

Funding

We thank the many study participants. We also thank Michael E. Hall for reviewing the manuscript. This work was supported by the National Institute on Drug Abuse grant numbers R01 DA035825, R01 DA036583 and R01 DA042090. Acknowledgments for the nicotine dependence studies are included in the Supplementary Information. Funding for lung cancer studies was provided by the National Cancer Institute grant number U19 CA148127.

Funders	Funder number
National Institute on Drug Abuse	R01 DA042090, R01 DA035825, R01DA012690, R01 DA036583
National Cancer Institute	U19 CA148127

Keywords

Journal Article

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Genomewide association study across European and AfricanAmerican ancestries identifies a SNP in DNMT3B contributing to nicotine dependenceFinal published version, 3.82 MBLicence: Article 25fa Dutch Copyright Act

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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., ... Johnson, E. O. (2018). Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Molecular Psychiatry, 23(9), 1911–1919. https://doi.org/10.1038/mp.2017.193

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

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

year = "2018",

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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. 1911–1919. https://doi.org/10.1038/mp.2017.193

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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 - 2018/9

Y1 - 2018/9

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.

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

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