Identifying Sources of Missing Heritability and Translating Genomic Variation in Nicotine Metabolism

Cigarette smoking continues to be a leading cause of preventable death. The rate of nicotine’s metabolic inactivation is mediated predominately by CYP2A6 enzyme activity, phenotyped by the nicotine metabolite ratio (NMR). The NMR is associated with several smoking behaviours, including differences in cessation outcomes and disease risk. The NMR is limited in that it requires specialized assays to run and cannot be quantified in non-regular smokers. These limitations prevent prediction of metabolizer status to evaluate disease-risk within these groups, or response to clinical drugs metabolized by CYP2A6. In contrast, genetic data is increasingly available in clinical studies and settings. Twin studies yield high heritability estimates for the NMR, indicating a genetic underpinning, yet known genetic variants explain only a fraction of the variation in the NMR. In this thesis, we explored potential sources of this missing heritability. With the rise of genome-wide association studies, novel variants associated with the NMR have been identified, but approaches to integrate these variants with known CYP2A6 variants have not been described. We developed weighted genetic risk scores (wGRSs) in both African- and in European-ancestral populations and contrasted these wGRSs to earlier genetic scoring and cross-ancestry approaches. Overall, we highlighted the ability of ancestry-specific wGRSs to replicate NMR-associated smoking cessation outcomes, such as demonstrating unique metabolizer by treatment interactions. Rare variants (minor allele frequency <1%) have been proposed to explain another portion of missing heritability. We used targeted sequencing to identify 38 novel CYP2A6 rare variants; novel variants were functionally characterized through in vivo, in silico, and in vitro approaches, and integrated into the wGRSs. On a population level, there is a minor contribution of CYP2A6 rare variants to NMR heritability; however, they provide an important contribution to the resulting prediction of metabolizer status for individuals genotyped with rare variants. Together these findings capture up to 33% and 34% of the genetic variation in the NMR in African and European populations, respectively. Overall, the research presented expands our knowledge of genetic variation in nicotine metabolism, providing insight into CYP2A6 genetic differences between ancestral populations, and enhancing our ability to use genetics to predict CYP2A6 activity.

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