Heroin addiction in African Americans: a hypothesis‐driven association study

Abstract

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.

Functional polymorphisms of the glutamate receptor N-methyl D-aspartate 2A gene are associated with heroin addiction

“…Other studies found similar heritability values in the context of substance use (Kendler et al, 1994;Tsuang et al, 1998;Kendler et al, 2003). Recent studies have suggested that polymorphisms in the N-methyl D-aspartate 2A (GRIN2A) gene may be associated with drug addiction, including alcohol and heroin addiction (Levran et al, 2009;Domart et al, 2012).…”

“…The present study examined the association between GRIN2A genes and heroin dependence in humans. Our results provide direct evidence that a genetic change in GRIN2A is linked to heroin addiction in humans, extending the list of variants that may affect the development of heroin addiction (Levran et al, 2009). Itokawa et al (2003b) previously identified a variable (GT)n repeat (rs3219790) in the 5'-regulatory region of GRIN2A, a gene encoding the NR2A subunit of the NMDA receptor complex.…”

“…Average observed repeat numbers and genotype distributions were significantly different in alcohol-dependent subjects compared to control subjects (Domart et al, 2012). Moreover, significantly more C-A-T (rs4587976-rs1071502-rs1366076) haplotypes were identified in African American heroin-addicted patients (Levran et al, 2009). However, it remains unknown whether these functional polymorphisms modulate the risk of heroin addiction.…”

An Association Study on the Glutamate Pathway GRIN2A Gene Polymorphisms with Heroin Dependence

“…Single nucleotide polymorphisms in GRIN2A, have been extensively studied in recent years and results have revealed them to be possibly associated with drug addiction, including alcohol and heroin [13][14][15][16]. A variable GTn repeat in the 5'-regulatory region of N-methyl-Daspartate GRIN2A subtype was identified and significantly associated with alcohol dependence [14,23].…”

“…The GRIN2A gene is located on chromosome 16p13.2 with twelve exons. Various studies investigated polymorphisms of the GRIN2A gene and suggested their association with heroin and alcohol addiction [13][14][15][16]. In a study on African-American population, GRIN2A was identified as the most potential candidate gene after screening 130 genes involved in heroin addiction [13].…”