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 four separate abuser/control comparisons, and appeared to add to evidence supporting roles for many of these genes with additional data from a comparison between nicotine depdendent and control samples. 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 resutls from studies of other addiction vulnerability genes, including NrCAM, BDNF and the cannabanoid CB1 and CB2 receptor genes.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Drug Abuse (NIDA)
• Type: Intramural Research (Z01)
• Project #: 1Z01DA000492-01
• Application #: 7321139
• Study Section: (MNRB)
• Support Year: 1
• Fiscal Year: 2006

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

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

Uhl, George R; Ishiguro, Hiroki; Onaivi, Emmanuel S et al. (2006) Molecular neurobiological methods in marijuana-cannabinoid research. Methods Mol Med 123:1-17

Drgon, Tomas; D'Addario, Claudio; Uhl, George R (2006) Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions. Am J Med Genet B Neuropsychiatr Genet 141:854-60

Liu, Qing-Rong; Drgon, Tomas; Johnson, Catherine et al. (2006) Addiction molecular genetics: 639,401 SNP whole genome association identifies many ""cell adhesion"" genes. Am J Med Genet B Neuropsychiatr Genet 141B:918-25

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