Genetic susceptibility to heroin addiction: a candidate gene association study

Abstract

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...

Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

“…Additionally, the CSNK1E SNP rs1534891 was associated with heroin addiction (Levran et al, 2008). Furthermore, coadministration of the casein kinase 1-d (Csnk1d)-preferring inhibitor PF-670462 with MA decreased locomotor activity and DARPP-32 phosphorylation in mice (Bryant et al, 2009b), and a similar result was observed following coadministration of PF-670462 with amphetamine in rats (Li et al, 2011).…”

“…Interestingly, we recently replicated the association of the CSNK1E SNP rs135745 with amphetamine-induced subjective euphoria (Veenstra-VanderWeele et al 2006) in healthy human volunteers in a new cohort of 282 subjects (Amy et al, unpublished data). The Csnk1e locus also affected opioid sensitivity (Figure 3) which, along with a previous association between a SNP in CSNK1E and heroin dependence (Levran et al, 2008), further implicates Csnk1e as a genetic regulator of sensitivity to drugs of abuse. Of particular note, a nearly identical genetic locus that we have identified (77)(78)(79)(80)(81)(82)(83) Mb in the present study) also regulates alcohol consumption in mice .…”

Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe

“…Thus, galanin interacts with 5-HT1A receptors, and galanin antagonists and agonists have anxiolytic and antidepressive effects in animal experiments (144)(145)(146)(147)(148)(149)(150)(151). Interestingly, association of genes encoding galanin and/or GalR3 has been reported for psychiatric phenotypes (152)(153)(154), including panic disorder (155), depression-related parameters (156)(157)(158), and nicotine dependence (159,160).…”

Brain galanin system genes interact with life stresses in depression-related phenotypes

“…previous genetic studies on humans that the galanin system is involved in psychiatric disorders including alcoholism/addiction (43)(44)(45)(46)(47), panic disorder (48,49), and chronic pain-associated depression (50). Furthermore, recent functional studies provided the first evidence that polymorphisms in a highly conserved genetic region upstream from the GAL gene regulates GAL expression in brain areas, such as the amygdala and hypothalamus, implicated in the pathogenesis of depression (51,52).…”