Based on our twin modelling, the heritability of NMR is 0.81. Although our novel independent SNPs capture a strikingly large fraction of this, major fraction still remains unaccounted for. This may be due to limitations of GWAS with lack of coverage of CYP2A6 duplications, translocations, and rare variants. Further, the high sequence homology between CYP2A6, CYP2A7, and CYP2A13 may prohibit detection of variants within homologous regions. SNP genotyping technologies using short probes will not be able to detect these variants with high specificity; most likely such variants will fail the HWE threshold, and thus will be excluded from analyses. In addition, limitations of statistical power result in inability to detect all relevant signals. In our GWAS meta-analysis we had high power to detect signals with common SNPs (MAF >5%) that have medium to high effect sizes. This is reflected in our top-SNPs, three of which are not only common but also have large effect sizes, and one that is rare (MAF = 0.03) but has a large effect size (beta = -1.08). We had very low power to detect signals
