Date of Award
Doctor of Philosophy (PhD)
Recent genome-wide association studies (GWAS) provide strong evidence for the contribution of a few specific genes to alcohol and nicotine dependence. Chapter 2 explores numerous previously identified candidate genes for alcohol dependence using a publicly available GWAS. I found that many candidate loci do not replicate, highlighting the utility of GWAS for focusing on disease associated genes. Chapters 3-5 dissect associations between three genome-wide significant genes and substance use disorders. Chapter 3 focuses on a functional variant in alcohol dehydrogenase (ADH) 1B. Through examining 1,550 adolescent drinkers in the Collaborative Study on the Genetics of Alcoholism (COGA), I extended adult findings by showing that this ADH1B variant protected against early drinking milestones. Furthermore, I provided evidence for a gene-by-environment interaction where best friends drinking eliminated this genetic protective effect, illustrating the important interplay between genetic and environmental factors in the development of drinking behaviors. Chapter 4 examines variation in the nicotine metabolizing cytochrome P450 gene CYP2A6. Previous studies show slow metabolizers smoke fewer cigarettes, but provide conflicting results on the role of CYP2A6 in nicotine dependence. Using a COGA young adult sample, I found that CYP2A6 metabolism was not associated with smoking initiation or daily smoking, but among daily smokers, slow metabolism was associated with increased risk of dependence. This association was replicated in an independent sample from the Collaborative Study of Nicotine Dependence, adding insight into the complex role of CYP2A6 across stages of smoking behaviors. Chapter 5 focuses on coding variation in the 5 nicotinic receptor subunit gene (CHRNA5), which harbors a nonsynonymous common variant robustly associated with nicotine dependence. I examined targeted sequence data of CHRNA5 from approximately 3,000 nicotine dependent cases and controls, with independent replication of common and low frequency variants in 12 studies. I found that common, low frequency, and rare CHRNA5 coding variants were independently associated with increased nicotine dependence risk. Incorporating coding variants beyond the well-studied common variant increased the variance in nicotine dependence explained by CHRNA5. Overall, this dissertation advances our understanding of targeted genes for substance use disorders by incorporating important environments, critical developmental periods, and rare variants.
Chair and Committee
Laura J. Bierut
Arpana Agrawal, Donald Conrad, Christina Gurnett, Jay Piccirillo,
Olfson, Emily, "Refining Associations between Targeted Genes and the Development of Substance Use Disorders" (2016). Arts & Sciences Electronic Theses and Dissertations. 792.
Permanent URL: https://doi.org/10.7936/K76H4FQK