One caveat to consider when performing pathway analysis is that the results obtained are biased, or at least restricted, to the biological knowledge that is incorporated into the GWAS, as well as its representation and modeling. This may explain the absence of any replicated GO term or KEGG pathway for the metabolism of nicotine. CYP2A6 encodes the enzyme that metabolizes approximately 70 to 80% of nicotine to cotinine [10], [40], [41]. A single SNP in this chromosomal region is typed by the Illumina Human 1 M chip.: rs3733829, which is in the first intron of EGLN2 located 40 kb downstream from CYP2A6 [10]. This SNP is not in high linkage disequilibrium with any other SNP included in the chip in the extended genetic region considered for the CYP2A6. Moreover, CYP2A6 is a complex locus involving structural and rare functional variants that are not well tagged by the SNPs included in the genotyping platforms. The UGT complex of genes, which catalyze nicotine and cotinine glucuronidation [34], were significant in both the OZALC-NAG and SAGE studies, and were identified among the other
