Determination of Genetic Mechanisms Underlying Smoking Addiction

Smoking poses significant threats to public health. Despite 50 years of prevention efforts, smoking remains the greatest cause of preventable diseases and deaths. Even though today’s users smoke fewer cigarettes than those 50 years ago, they are at higher risk of developing lung cancer because of changes in cigarettes. Our group and others have shown strong evidence for the involvement of genetics in nicotine dependence (ND), with an average heritability of 0.56. This dissertation contributes to our understanding of the genetic structure of smoking from four perspectives. In the first study, leveraging computational efficiency of the GPU-based Generalized Multifactor Dimensionality Reduction (GMDR-GPU) program, we detected variants in genes encoding the 5-HT3AB receptors (HTR3A and HTR3B) and the serotonin transporter (SLC6A4) interactively affecting etiology of alcohol, cocaine, and nicotine dependence, although their individual effect was weak. In the second study, targeted next-generation sequencing was used to discover rare variants from ND candidate genes. Although none of the genotyped common variants showed significant association with different smoking measures, the weighted sum statistic (WSS) and combined sum test results indicated that rare variants alone or combined with common variants in a subset of candidate genes contribute significantly to the risk of ND. In the third study, we developed an ND genetic susceptibility map based on the results obtained by the approaches commonly used in recent years, which include genome-wide linkage, candidate gene association, GWAS, and targeted sequencing studies. Converging and diverging results from these empirical approaches have elucidated a preliminary genetic architecture of this intractable psychiatric disorder and yielded new hypotheses on ND etiology. In the final study, cis-expression and methylation quantitative trait loci (eQTL and mQTL) were mapped for the candidate genes ascertained in the third study using human brain tissues. Among the one eQTL and two mQTLs determined, for the first time we showed that the minor allele of one variation significantly decreased methylation levels at one gene, reduced expression levels of another, and lowered percentage of smokers all in a dominant way for the same cohort. The studies presented in this dissertation provide a variety of novel insights into the genetic mechanisms of smoking addiction; and perhaps more importantly, new ideas and methods to study other complex traits/diseases are generated.