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

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Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2018-Sep-01 , DOI: 10.1038/mp.2017.193
D B Hancock ₁ , Y Guo ₂ , G W Reginsson ₃ , N C Gaddis ₄ , S M Lutz ₅ , R Sherva ₆ , A Loukola ₇ , C C Minica ₈ , C A Markunas ₁ , Y Han ₉ , K A Young ₁₀ , D F Gudbjartsson _{3,

11} , F Gu ₁₂ , D W McNeil _{13,

14} , B Qaiser ₇ , C Glasheen ₁ , S Olson ₁₅ , M T Landi ₁₂ , P A F Madden ₁₆ , L A Farrer _{6,

17,

18,

19,

20} , J Vink _{8,

21} , N L Saccone ₂₂ , M C Neale _{23,

24} , H R Kranzler _{25,

26} , J McKay ₂₇ , R J Hung ₂₈ , C I Amos ₉ , M L Marazita ₂₉ , D I Boomsma ₈ , T B Baker ₃₀ , J Gelernter _{31,

32,

33,

34} , J Kaprio _{7,

35} , N E Caporaso ₁₂ , T E Thorgeirsson ₃ , J E Hokanson ₁₀ , L J Bierut ₁₆ , K Stefansson ₃ , E O Johnson ₃₆

Affiliation

Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.
Center for Genomics in Public Health and Medicine, RTI International, Research Triangle Park, NC, USA.
deCODE Genetics/Amgen, Reykjavik, Iceland.
Research Computing Division, RTI International, Research Triangle Park, NC, USA.
Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
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.
Department of Psychology, West Virginia University, Morgantown, WV, USA.
Department of Dental Practice and Rural Health, West Virginia University, Morgantown, WV, USA.
Public Health Informatics Program, eHealth, Quality and Analytics Division, RTI International, Research Triangle Park, NC, USA.
Department of Psychiatry, Washington University, St. Louis, MO, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Behavioural Science Institute, Radboud University, Nijmegen, The Netherlands.
Department of Genetics, Washington University, St. Louis, MO, USA.
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Crescenz VA Medical Center, Philadelphia, PA, USA.
International Agency for Research on Cancer, World Health Organization, Lyon, France.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, ON, Canada.
Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
VA CT Healthcare Center, Department of Psychiatry, West Haven, CT, USA.
Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, NC, USA.

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.

中文翻译：

跨欧洲和非裔美国人血统的全基因组关联研究发现 DNMT3B 中的一个 SNP 会导致尼古丁依赖。

吸烟是全世界可预防死亡的主要原因。尼古丁依赖会降低戒烟的可能性，它是一种遗传性状，与尼古丁乙酰胆碱受体基因和其他基因座的序列变异有牢固的关联。为了寻找其他位点，我们对尼古丁依赖进行了全基因组关联研究 (GWAS) 荟萃分析，15 项研究共涉及 38,602 名吸烟者（28,677 名欧洲人/欧洲裔美国人和 9925 名非洲裔美国人）。在这项有史以来最大规模的尼古丁依赖 GWAS 荟萃分析和有史以来最大规模的针对任何吸烟表型的跨祖先 GWAS 荟萃分析中，我们再次确认了众所周知的 CHRNA5-CHRNA3-CHRNB4 基因，并进一步在 DNA 中产生了一种新的关联。甲基转移酶基因DNMT3B。内含子 DNMT3B rs910083-C 等位基因（频率=44-77%）与尼古丁依赖风险增加相关，P=3.7 × 10 ^-8 （比值比 (OR)=1.06 和 95% 置信区间 (CI)=1.04- 1.07（严重依赖与轻度依赖）。英国生物银行 (N=48,931) 使用重度吸烟与从不吸烟作为代理表型独立证实了该关联（P=3.6 × 10 ^-4 、OR=1.05 和 95% CI=1.02-1.08）。在国际肺癌联盟中，Rs910083-C 还与鳞状细胞肺癌风险增加相关（N=60,586，荟萃分析 P=0.0095，OR=1.05，95% CI=1.01-1.09）。此外，rs910083-C 被认为是与胎儿脑中较高的 DNMT3B 甲基化相关的顺式甲基化数量性状基因座（QTL）变异（N = 166，P = 2.3 × 10 ^-26 ）和与较高的 DNMT3B 甲基化相关的顺式表达 QTL 变异。来自基因型组织表达项目的成人小脑中的 DNMT3B 表达（N=103，P=3。0 × 10 ^-6 ) 和独立的 Brain eQTL 年鉴 (N=134, P=0.028)。这种新型 DNMT3B 顺式作用 QTL 变体强调了大脑中遗传影响调节对尼古丁依赖、大量吸烟和随之而来的肺癌风险的重要性。

更新日期：2017-10-11

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