MZ and DZ twins of FinnTwin12 and FinnTwin16 cohorts yielded a heritability estimate of 0.81 for NMR, confirming that genetic effects are major determinants of inter-individual variance in NMR. This estimate is higher than previous estimates obtained in an experimental setting [16], perhaps due to less heterogeneity in the Finnish sample. Our aim was to identify novel genetic variants affecting nicotine metabolism. We utilized NMR, a biomarker of nicotine metabolism, in a GWAS meta-analysis of three Finnish cohorts, and identified association on 19q13.2. This locus harbours a number of genes, including several members of the cytochrome P450 gene family. Three independent genome-wide significant signals were detected, all located either within or in the immediate vicinity of CYP2A6, the gene encoding the main metabolic enzyme for nicotine. A fourth independent signal in CYP2A6 emerged in one of the samples (FINRISK2007); however, this was not seen in the meta-analysis. The minor alleles of all of the independent variants associated with decreased NMR values, i.e. decreased nicotine clearance rate. All the independent variants are novel signals and have not been previously been highlighted in any smoking-related GWAS.
