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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.
Afiliação
  • Hancock DB; Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA. dhancock@rti.org.
  • Guo Y; Center for Genomics in Public Health and Medicine, RTI International, Research Triangle Park, NC, USA.
  • Reginsson GW; deCODE Genetics/Amgen, Reykjavik, Iceland.
  • Gaddis NC; Research Computing Division, RTI International, Research Triangle Park, NC, USA.
  • Lutz SM; Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Sherva R; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
  • Loukola A; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Minica CC; Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
  • Markunas CA; Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
  • Han Y; Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • Young KA; Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Gudbjartsson DF; deCODE Genetics/Amgen, Reykjavik, Iceland.
  • Gu F; Department of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
  • McNeil DW; Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA.
  • Qaiser B; Department of Psychology, West Virginia University, Morgantown, WV, USA.
  • Glasheen C; Department of Dental Practice and Rural Health, West Virginia University, Morgantown, WV, USA.
  • Olson S; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Landi MT; Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
  • Madden PAF; Public Health Informatics Program, eHealth, Quality and Analytics Division, RTI International, Research Triangle Park, NC, USA.
  • Farrer LA; Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA.
  • Vink J; Department of Psychiatry, Washington University, St. Louis, MO, USA.
  • Saccone NL; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
  • Neale MC; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
  • Kranzler HR; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
  • McKay J; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
  • Hung RJ; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Amos CI; Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
  • Marazita ML; Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.
  • Boomsma DI; Department of Genetics, Washington University, St. Louis, MO, USA.
  • Baker TB; Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
  • Gelernter J; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
  • Kaprio J; Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • Caporaso NE; Crescenz VA Medical Center, Philadelphia, PA, USA.
  • Thorgeirsson TE; International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Hokanson JE; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, ON, Canada.
  • Bierut LJ; Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • Stefansson K; Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Johnson EO; Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
Mol Psychiatry ; 23(9): 1911-1919, 2018 09.
Article em En | MEDLINE | ID: mdl-28972577
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tabagismo / DNA (Citosina-5-)-Metiltransferases Tipo de estudo: Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tabagismo / DNA (Citosina-5-)-Metiltransferases Tipo de estudo: Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2018 Tipo de documento: Article