UC San Diego

Relative to other substances of abuse (e.g. alcohol, tobacco) the mechanisms which underlie the onset and progression of methamphetamine use disorders (METH) and their consequences (e.g. HIV risk behavior) are unclear. The purpose of this dissertation was to elucidate potential mechanisms using a systems biology and ecological approach in which, genetic, neurocognitive, and behavioral data were examined and explored in the context of METH and HIV. First a synthesis of the current genetic association literature was conducted to provide a systematic and quantitative review of the genetic epidemiology of METH use disorders. Then utilizing results obtained from the synthesis and existing data on 400 adults with and without HIV-infection and/or METH dependence, a series of analyses were undertaken to replicate putative genetic markers for METH dependence as well as to examine and explore genetic, neurocognitive and contextual factors for HIV risk behaviors. All subjects underwent a comprehensive clinical characterization that included: demographic information, standardized medical examination, neurocognitive and psychiatric assessment as well as HIV risk behavior assessment. Available blood samples were used for DNA extraction and genotyping. Synthesis of the literature uncovered 39 genes, of which 18 were found to have a putative genotypic, allelic, and/ or haplotypic association with METH use disorders, predominately in Asian populations. Case-control analysis among a diverse sample of African-Americans, Hispanics, and Caucasians for six of the putative and three novel genes suggested considerable ethnic divergence for METH dependence. Cross-sectional analyses revealed several complex associations between genetic [i.e. catechol-o- methyltransferase (COMT)], neurocognitive (i.e. executive functioning), and contextual (i.e. METH, HIV) factors on HIV risk behavior. Analyses suggested that dependent on a subjects COMT genotype and context, executive functioning and HIV risk behavior profiles can be significantly different, respectively. Findings provide support for further validation of candidate genes for METH dependence reported among Asian populations across other ethnic/ ancestral groups as well as, examination of gene-context (i.e. gene-environment) associations and neurocognitive factors to better understand the complexity of HIV risk behavior