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

by | Addiction

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017193a.html?foxtrotcallback=true

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

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.

Comment;

THIS is EXCITING SCIENCE!!  We know that genes strongly influence diseases such as addiction.  If you don’t have the genetic material for addiction you have a low to no risk of becoming addicted when exposed to drugs of abuse.  If you DO have the genes, look out!

We know that when the human genome was first sequenced, the majority of our DNA was initially labeled as “junk DNA”. This DNA did NOT code for proteins.

Now we know that this “junk DNA” contained regulatory regions of our genome/DNA string.  Environmental factors would “turn on” and “turn off” expression of certain stretches of DNA to make or not make their respective proteins.  There are other means of gene regulation as well, microRNA, other environmental factors interact within the cell to help regulate expression of DNA in the nucleus of the cell.  Together, these cells form organs, if that organ is the brain, it forms behaviors!  We’re breaking the understanding of behavior down to the chemical level–this is WAY COOL!  So much more to do, but we’re LEARNING.  This stuff is fascinating–so much more to be revealed!  We’ve identified a SNP for nicotine dependence.  I’ll be there are others for opioid tolerance, as well as general risk of addiction and preferences for certain types of abuseable substances & behaviors (sex, food, gambling…)

Dr. Raymond Oenbrink
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