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Gene That Influences Nicotine Dependence Identified

Summary: Researchers have identified a genetic variant associated with an increased risk of nicotine dependence.

Source: RTI.

A DNA variant—located in the DNMT3B gene and commonly found in people of European and African descent—increases the likelihood of developing nicotine dependence, smoking heavily, and developing lung cancer, according to a new study led by RTI International.

Nearly 1 billion people smoke and 6 million premature deaths occur worldwide each year from cigarette smoking, according to the World Health Organization. Smoking is the leading cause of preventable death and one person dies approximately every 6 seconds from smoking-related causes, according to the WHO.

The new study, published in Molecular Psychiatry, is the largest genome-wide association study of nicotine dependence. Researchers studied more than 38,600 former and current smokers from the United States, Iceland, Finland, and the Netherlands.

“This new finding widens the scope of how genetic factors are known to influence nicotine dependence,” said Dana Hancock, Ph.D., genetic epidemiologist at RTI and lead author of the study. “The variant that we identified is common, occurring in 44 percent of Europeans or European Americans and 77 percent of African Americans, and it exerts important effects on gene regulation in human brain, specifically in the cerebellum, which has long been overlooked in the study of addiction.”

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The genetic variant was linked to an increased risk of nicotine dependence by testing nearly 18 million variants across the genome for association with nicotine dependence. The variant was also tested in independent studies and found to associate with heavier smoking and with increased risk of lung cancer. Image in the public domain.

The genetic variant was linked to an increased risk of nicotine dependence by testing nearly 18 million variants across the genome for association with nicotine dependence. The variant was also tested in independent studies and found to associate with heavier smoking and with increased risk of lung cancer.

About this neuroscience research article

Funding: Researchers representing more than 20 organizations and institutions contributed to this study. The study was supported in part by the National Institute on Drug Abuse.

Source: RTI
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence” by 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 and E O Johnson in Molecular Psychiatry. Published online October 3 2017 doi:10.1038/mp.2017.193

Cite This NeuroscienceNews.com Article
RTI “Gene That Influences Nicotine Dependence Identified.” NeuroscienceNews. NeuroscienceNews, 11 October 2017.
<http://neurosciencenews.com/genetics-nicotine-addiction-7726/>.
RTI (2017, October 11). Gene That Influences Nicotine Dependence Identified. NeuroscienceNews. Retrieved October 11, 2017 from http://neurosciencenews.com/genetics-nicotine-addiction-7726/
RTI “Gene That Influences Nicotine Dependence Identified.” http://neurosciencenews.com/genetics-nicotine-addiction-7726/ (accessed October 11, 2017).

Abstract

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

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.

“Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence” by 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 and E O Johnson in Molecular Psychiatry. Published online October 3 2017 doi:10.1038/mp.2017.193

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