Although only variants in CYP2A6 were highlighted as independent signals, other interesting genes, such as CYP2B6, CYP2A7, EGLN2, and NUMBL, reside within the 19q13 locus, and showed genome-wide significant association in our GWAS meta-analysis. Our top-SNP in CYP2B6 (rs7260329) has been highlighted in the large GWAS meta-analysis of CPD [14]. CYP2B6 can also catalyze nicotine metabolism to cotinine and to nornicotine [9]; the CYP2B6 gene sits adjacent to CYP2A6 and they share some common regulation. CYP2B6 also metabolizes several other drugs of abuse, as well as bupropion, an atypical antidepressant also used as a smoking cessation aid [5]. Several functional CYP2B6 variants have been identified. The most prevalent and clinically important variant is CYP2B6*6, characterized as a haplotype consisting of two linked non-synonymous variants CYP2B6*4 (rs2279343 (K262R)) and CYP2B6*9 (rs3745274 (Q172H)), resulting in a splice site variant with reduced function [61]. In the current study the non-synonymous SNPs defining CYP2B6*4, CYP2B6*9, as well as CYP2B6*5 (rs3211371 (R487C)) did not show genome-wide significant results, but were in high LD with the top-SNP in CYP2B6 (rs7260329) (S9 Fig). Further, rs7260329 shows modest
