Our top-SNP (rs56113850) is located in intron 4 of CYP2A6, has a high minor allele frequency (MAFFINRISK = 0.44) and a prominent effect size (beta = -0.65), and alone accounts for a substantial percentage of variance (14–23%) in NMR in the three Finnish cohorts. Our second independent SNP (rs113288603) is located 5.9 kb upstream of CYP2A6, seems to be enriched in the Finnish population (MAFFINRISK = 0.15 vs. MAFEUR = 0.09), has a small effect size (beta = -0.02), and accounts for less than 1% of variance in NMR in the three cohorts. Neither of these variants has predicted functional consequences. Interestingly, our data support a plausible interplay between rs113288603 and rs56113850, as the effect sizes significantly increase when the other SNP is added to the model. These findings are in line with our GWAS data, as rs113288603 shows no association in any of the cohort-specific GWAS or in the meta-analysis, but in an analysis conditioned on rs56113850 it emerges as the second independent genome-wide significant SNP. The plausible mechanism underlying the interplay remains to be determined.
