Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human Genetics

First Advisor

Danielle M. Dick

Abstract

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history has not yet been reported. These studies aim to explore the aggregate impact of multiple genetic variants with small effect sizes on risk prediction in order to provide a clinical interpretation of genetic contributions to AD. Data simulations showed that given AD’s prevalence and heritability, a risk prediction model incorporating all genetic contributions would have an area under the receiver operating characteristic curve (AUC) approaching 0.80, which is often a target AUC for screening. Adding additional environmental factors could increase the AUC to 0.95. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we used several different sources to capture genetic information associated with AD in discovery samples, and then tested genetic sum scores created based on this information for predictive accuracy in validation samples. Scores were assessed separately for single nucleotide polymorphisms (SNPs) associated in candidate gene studies and in GWAS analyses. Candidate gene sum scores did not exhibit significant predictive accuracy, but SNPs meeting less stringent p-value thresholds in GWAS analyses did, ranging from mean estimates of 0.549 for SNPs meeting p<0.01 to 0.565 for SNPs meeting p<0.50. Variants associated with subtypes of AD showed that there is similarly modest and significant predictive ability for an externalizing subtype. Scores created based on all individual SNP effects in aggregate across the entire genome accounted for 0.46%-0.57% of the variance in AD symptom count, and have AUCs of 0.527 to 0.549. Additional covariates and environmental factors that are correlated with AD increased the AUC to 0.865. Family history was a better classifier of case-control status than genetic sum scores, with an AUC of 0.686 in COGA and 0.614 in SAGE. This project suggests that SNPs from candidate gene studies and genome-wide association studies currently have limited clinical validity, but there is potential for enhanced predictive ability with better detection of genetic factors contributing to AD.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

September 2012

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