This largest-ever GWAS meta-analysis for nicotine dependence, and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, identified rs910083 as a novel SNP that regulates DNMT3B in human brain and contributes to risks of nicotine dependence and heavy smoking. Rs910083 was discovered via meta-analysis of two ancestry groups; the association signal includes SNPs in high LD with rs910083 across the COMMD7, DNMT3B, and MAPRE1 genes in EUR ancestry, but LD is localized to the DNMT3B gene in AA ancestry. Moreover, rs910083 was implicated as a cis-acting QTL SNP that influences DNMT3B DNAm in fetal brain and DNMT3B RNAexp in adult cerebellum, with the C allele being associated with higher DNAm and RNAexp levels. While this pattern might contrast the traditional view of higher DNAm being correlated with lower RNAexp, the observed effects reflect temporal and spatial differences, thus limiting our ability to draw direct correlations. Nonetheless, genome-wide QTL comparisons in human brain have shown that almost half of SNPs that act as both an eQTL and meQTL show the same direction of association for DNAm and RNAexp,41 as we observed
