Genetic Approaches To Characterizing Drug Responses And

Uhl, George Richard

Abstract

Individual differences in drug abuse vulnerabilities among humans are likely to display genetic as well as environmental components. During this year, these investigators continued to explore possible roles of allelic variants at candidate gene loci in possibly contributing to human individual differences in drug abuse vulnerability. We published the first report of convergence of the several genome scanning approaches to identifying previously-unanticipated gene loci conferring drug abuse vulnerabilities. We continued to make major advances in providing simulations and modeling for the power of genome-wide and focused association/linkage-disequilibrium based genome scanning. Work during this year provided replication and extension of identificaiton of candidate regions on several human chromosomes using high-density SNP and SSLP-based linkage-disequilibrium based genome scanning. Data is consistent with the emerging models that genetic influences are polygenic, with few major gene influences. Several chromosomal regions previously nomninated by our studies have been replicated in new work published during this year. Fine mapping studies have identified particular haplotypes at several gene loci that represent the strongest candidates for addiction vulnerability genes in humans.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Drug Abuse (NIDA)
• Type: Intramural Research (Z01)
• Project #: 1Z01DA000401-06
• Application #: 6830620
• Study Section: (MNRB)
• Support Year: 6
• Fiscal Year: 2003

Institution

• Name: National Institute on Drug Abuse
• Country: United States

Publications

Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko et al. (2009) mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons. Neurosci Lett 453:62-7

Saccone, Scott F; Bierut, Laura J; Chesler, Elissa J et al. (2009) Supplementing high-density SNP microarrays for additional coverage of disease-related genes: addiction as a paradigm. PLoS One 4:e5225

Johnson, Catherine; Drgon, Tomas; McMahon, Francis J et al. (2009) Convergent genome wide association results for bipolar disorder and substance dependence. Am J Med Genet B Neuropsychiatr Genet 150B:182-90

Uhl, George (2008) Dr George Uhl speaks to Shreeya Nanda, commissioning editor. Pharmacogenomics 9:813-7

Onaivi, Emmanuel S; Ishiguro, Hiroki; Gong, Jian-Ping et al. (2008) Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS ONE 3:e1640

Ishiguro, Hiroki; Gong, Jian-Ping; Hall, F Scott et al. (2008) Association of PTPRB gene polymorphism with drug addiction. Am J Med Genet B Neuropsychiatr Genet 147B:1167-72

Uhl, George R; Drgon, Tomas; Liu, Qing-Rong et al. (2008) Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry 65:345-55

Uhl, George R; Drgon, Tomas; Johnson, Catherine et al. (2008) ""Higher order"" addiction molecular genetics: convergent data from genome-wide association in humans and mice. Biochem Pharmacol 75:98-111

Hishimoto, Akitoyo; Liu, Qing-Rong; Drgon, Tomas et al. (2007) Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Hum Mol Genet 16:2880-91

Uhl, George R; Liu, Qing-Rong; Drgon, Tomas et al. (2007) Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs. BMC Genet 8:10