Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in noncoding regions of the genes encoding the mu (OPRM1; rs510769 and rs3778151), kappa (OPRK1; rs6473797) and delta (OPRD1; rs2236861, rs2236857 and rs3766951) opioid receptors; the neuropeptide galanin (GAL; rs694066); the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multilocus genotype patterns showed nominally significant associations (e.g. OPRM1; P 5 0.0006 and CSNK1E; P 5 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P 5 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction, which is worthy of future study. Heroin addiction is a chronic relapsing disease characterized by compulsive drug seeking, drug abuse, tolerance and physical dependence. It is treated by methadone, buprenorphine and behavioral therapy. Heroin addiction is part of group of addictions (e.g. cocaine, alcohol and nicotine) that constitute a worldwide public health crisis. The genetic contribution to vulnerability to develop heroin addiction is 40-60%, suggesting a complex inheritance mode in which multiple genes exert a small effect, along with the environment (Kendler et al. 2003;Tsuang et al. 1996Tsuang et al. , 1998. ). These include variants in the genes encoding the mu and kappa opioid receptors, dopamine receptors D2 and D4, serotonin receptor 1B, gamma-aminobutryic acid (GABA) receptor subunit gamma 2, catechol-O-methyltransferase, period circadian protein (PER3), proenkephalin, proopiomelanocortin, tryptophan hydroxylase 2 and brain-derived neurotrophic factor.To identify genetic variants that underlie heroin addiction, we performed a candidate gene case-control association study using a single nucleotide polymorphism (SNP) array that was designed by the group of D. Goldman at the National Institute of Alcohol Abuse and Alcoholism (NIAAA). This approach is based on physiological hypotheses and the genes were selected based on their function (e.g. drug receptors, neurotransmitters, transporters and drug metabolism enzymes) and related pathways (e.g. reward modulation, behavioral control, cognitive function, signal transduction and stress response). In order to maximize the power of the study, the cases were selected from the extreme margin of the specific phenotype range (e.g. severe heroin a...

Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify gene variants associated with heroin addiction in African Americans. The emphasis was on genes involved in reward modulation, behavioral control, cognitive function, signal transduction and stress response. We have performed a case-control association analysis by screening with 1350 variants of 130 genes. The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse. Single nucleotide polymorphism (SNP), haplotype and multi-SNP genotype pattern analyses were performed. Seventeen SNPs showed point-wise significant association with heroin addiction (nominal P < 0.01). These SNPs are from genes encoding several receptors: adrenergic (ADRA1A), arginine vasopressin (AVPR1A), cholinergic (CHRM2), dopamine (DRD1), GABA-A (GABRB3), glutamate (GRIN2A) and serotonin (HTR3A) as well as alcohol dehydrogenase (ADH7), glutamic acid decarboxylase (GAD1 and GAD2), the nucleoside transporter (SLC29A1) and diazepambinding inhibitor (DBI). The most significant result of the analyses was obtained for the GRIN2A haplotype G-A-T (rs4587976-rs1071502-rs1366076) with protective effect (P uncorrected = 9.6E-05, P corrected = 0.058). This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction. Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability.