Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Marissa A. Ehringer

Second Advisor

Jerry A. Stitzel

Third Advisor

Matthew B. McQueen

Fourth Advisor

Michael C. Stallings

Fifth Advisor

John E. Hokanson

Abstract

Alcohol and tobacco use are highly heritable and widespread problems. There is a substantial genetic correlation between alcohol dependence (AD) and nicotine dependence (ND), suggesting the same genetic factors explain much of the variation in these disorders. The purpose of these studies was to investigate aspects of genetic influence on alcohol and nicotine behaviors in human populations.

Using single nucleotide polymorphisms (SNPs), two candidate gene studies were performed to assess associations with alcohol abuse and dependence (AAD), alcohol consumption (AC), and conduct disorder (CD). The first study involved a replication of SNPs in GABRA2; although one SNP was associated with AAD and CD, previous findings with another well-studied SNP were not replicated. In the second study, GRM7 was investigated. Both the single SNP analyses as well as the gene-based test employed failed to find an association between common variants in GRM7 and AC.

In a separate series of analyses, gene-based tests were utilized to test for association with drug behaviors in a manually-curated set of genes. The first series of analyses focused on ND and cigarettes per day (CPD) in European Americans (EAs) and African Americans (AAs). Although different genes were identified for CPD and ND for each ethnic group, genes associated with CPD in EAs tended to be associated with ND in AAs, and vice versa. The second series of analyses focused on AD in EAs. Although many of the genes associated with AD in EAs were different from those associated with nicotine behaviors in EAs, one gene, DNAJA3, was associated with both drug behaviors in EAs.

Targeted sequencing of genes showing preliminary association with AD or ND was performed in a small sample. Rare variants identified in each gene were collapsed into sets to test for association. One set in FGFR2 was associated with AD after correction for multiple testing.

In conclusion, SNP associations, GWAS, and sequencing studies can be utilized to investigate genetic risk factors for AD and ND and suggest future avenues for investigation. These studies demonstrate the importance of large samples and using multiple analytical approaches in order to weigh the reproducibility of each study.

Included in

Genetics Commons

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