Understanding addiction vulnerability genes

Uhl, George Richard

Abstract

Addiction vulnerability genes include those that are likely to harbor allelic variants that contribute to human individual differences in vulnerability to addictions. During this year, we identified more than 80 such genes based on the covergences between nominally-positive data derived from five separate abuser/control comparisons. We added to evidence supporting roles for many of these genes with additional data from several comparisons between nicotine depdendent and control samples. We added additional support from comparisons between smokers who were successful vs unsuccessful in quitting in clinical trials. Genes identified in this fashion include a disproportionate number of genes whose products are involved in cell adhesion molecule actions. During this year we identified the frequent functional variations at the loci that contain these genes, including splicing variants, missense variants, veriations in 3 and 5 untranslated regions, variations in 5 flanking sequences and variaitons in natural antisense tanscripts. A number of these variations appear to be closely associaiated with addiction vulnerability haplotypes. During the year we reported results from studies of other addiction vulnerability genes, including a transporter gene.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Drug Abuse (NIDA)
• Type: Intramural Research (Z01)
• Project #: 1Z01DA000492-02
• Application #: 7593296
• Support Year: 2
• Fiscal Year: 2007
• Total Cost: $423,424

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

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

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

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

Ishiguro, Hiroki; Liu, Qing-Rong; Gong, Jian-Ping et al. (2006) NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice. Neuropsychopharmacology 31:572-84

Onaivi, Emmanuel S; Ishiguro, Hiroki; Sejal, Patel et al. (2006) Methods to study the behavioral effects and expression of CB2 cannabinoid receptor and its gene transcripts in the chronic mild stress model of depression. Methods Mol Med 123:291-8

Gong, Jian-Ping; Onaivi, Emmanuel S; Ishiguro, Hiroki et al. (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10-23

Liu, Qing-Rong; Lu, Lin; Zhu, Xu-Guang et al. (2006) Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res 1067:1-12

Fride, Ester; Perchuk, Alex; Hall, F Scott et al. (2006) Behavioral methods in cannabinoid research. Methods Mol Med 123:269-90

Johnson, Catherine; Drgon, Tomas; Liu, Qing-Rong et al. (2006) Pooled association genome scanning for alcohol dependence using 104,268 SNPs: validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism. Am J Med Genet B Neuropsychiatr Genet 141B:844-53