title: Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence.
abstract: BACKGROUND
  Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants.
  
  
  OBJECTIVE
  To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients.
  
  
  METHODS
  303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA).
  
  
  CONCLUSIONS
  In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vereczkei
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Demetrovics
authors.forename: Anna
authors.initials: A
authors.lastname: Szekely
authors.forename: Peter
authors.initials: P
authors.lastname: Sarkozy
authors.forename: Peter
authors.initials: P
authors.lastname: Antal
authors.forename: Agnes
authors.initials: A
authors.lastname: Szilagyi
authors.forename: Maria
authors.initials: M
authors.lastname: Sasvari-Szekely
authors.forename: Csaba
authors.initials: C
authors.lastname: Barta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006556:Heroin Dependence / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015999:Multivariate Analysis; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; D002394:Catechol O-Methyltransferase; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases