No DNMT3B variants have been implicated previously for any substance use disorder (SUD) phenotype. Upstream of DNMT3B, chromosome 20q11 also harbors the nucleolar protein 4-like (NOL4L) gene, which was reported at genome-wide significance for heavy vs never smoking in the UK Biobank for the indel rs57342388.24 This indel was associated at meta-analysis P=0.0017 in our study (Table 1): OR (95% CI)=1.04 (1.02–1.07) for severe vs mild dependence for the insertion allele, consistent with the prior result. Rs57342388 is located 216 kb upstream of our top DNMT3B SNP rs910083. The two variants are weakly correlated (r2=0.11 in 1000G EUR where MAF=2% for rs57342388 vs 18% for rs910083, r2=0.0022 in AFR where MAF=19% vs 42%) but are in moderate to high LD (D′=0.57 in EUR, D′=1 in AFR). In follow-up testing with both SNPs included in the same model, both were associated with nicotine dependence (meta-analysis P=1.7×10−6 for rs910083 and 8.3×10−3 for rs57342388), showing that our observed DNMT3B association signal is not explained by the previously reported NOL4L signal.
