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1.
Tsuang  MTLyons  MJMeyer  JMDoyle  TEisen  SAGoldberg  JTrue  WLin  NToomey  REaves  L Co-occurrence of abuse of different drugs in men: the role of drugspecific and shared vulnerabilities.  Arch Gen Psychiatry. 1998;55967- 972PubMedGoogle ScholarCrossref
2.
Maldonado  RSaiardi  AValverde  OSamad  TARoques  BPBorrelli  E Absence of opiate rewarding effects in mice lacking dopamine D2 receptors.  Nature. 1997;388586- 589PubMedGoogle ScholarCrossref
3.
Elmer  GIPieper  JORubinstein  MLow  MJGrandy  DKWise  RA Failure of intravenous morphine to serve as an effective instrumentalreinforcer in dopamine D2 receptor knock-out mice.  J Neurosci. 2002;22RC224PubMedGoogle Scholar
4.
Thanos  PKVolkow  NDFreimuth  PUmegaki  HIkari  HRoth  GIngram  DKHitzemann  R Overexpression of dopamine D2 receptors reduces alcohol self-administration.  J Neurochem. 2001;781094- 1103PubMedGoogle ScholarCrossref
5.
Volkow  NDWang  GJMaynard  LFowler  JSJayne  BTelang  FLogan  JDing  YSGatley  SJHitzemann  RWong  CPappas  N Effects of alcohol detoxification on dopamine D2 receptors in alcoholics:a preliminary study.  Psychiatry Res. 2002;116163- 172PubMedGoogle ScholarCrossref
6.
Litt  MKramer  PKort  EFain  PCox  SRoot  DWhite  RWeissenbach  JDonis-Keller  HGatti  RWeber  JNakamura  YJulier  CHayashi  KSpurr  NDean  MMandel  JKidd  KKruse  TRetief  ABale  AMeo  TVergnaud  GWarren  SWilland  HF The CEPH consortium linkage map of human chromosome 11.  Genomics. 1995;27101- 112PubMedGoogle ScholarCrossref
7.
Grandy  DKLitt  MAllen  LBunzow  JRMarchionni  MMakam  HReed  LMagenis  RECivelli  O The human dopamine D2 receptor gene is located on chromosome 11 atq22-q23 and identifies a TaqI RFLP.  Am J Hum Genet. 1989;45778- 785PubMedGoogle Scholar
8.
Gelernter  JO'Malley  SRisch  NKranzler  HRKrystal  JMerikangas  KKennedy  JLKidd  KK No association between an allele at the D2 dopamine receptor gene (DRD2)and alcoholism.  JAMA. 1991;2661801- 1807PubMedGoogle ScholarCrossref
9.
Gelernter  JGoldman  DRisch  N The A1 allele at the D2 dopamine receptor gene and alcoholism: a reappraisal.  JAMA. 1993;2691673- 1677PubMedGoogle ScholarCrossref
10.
Noble  EPSyndulko  KFitch  RJRitchie  TBohlman  MCGuth  PSheridan  PJMontgomery  AHeinzmann  CSparkes  RS D2 dopamine receptor TaqI A alleles in medically ill alcoholic andnonalcoholic patients.  Alcohol Alcohol. 1994;29729- 744PubMedGoogle Scholar
11.
Noble  EP The DRD2 gene in psychiatric and neurological disorders and its phenotypes.  Pharmacogenomics. 2000;1309- 333PubMedGoogle ScholarCrossref
12.
Blum  KNoble  EPSheridan  PJMontgomery  ARitchie  TJagadeeswaran  PNogami  HBriggs  AHCohn  JB Allelic association of human dopamine D2 receptor gene in alcoholism.  JAMA. 1990;2632055- 2060PubMedGoogle ScholarCrossref
13.
Parsian  ATodd  RDDevor  EJO'Malley  KLSuarez  BKReich  TCloninger  CR Alcoholism and alleles of the human D2 dopamine receptor locus: studiesof association and linkage.  Arch Gen Psychiatry. 1991;48655- 663PubMedGoogle ScholarCrossref
14.
Comings  DEMuhleman  DAhn  CGysin  RFlanagan  SD The dopamine D2 receptor gene: a genetic risk factor in substance abuse.  Drug Alcohol Depend. 1994;34175- 180PubMedGoogle ScholarCrossref
15.
Heinz  ASander  THarms  HFinckh  UKuhn  SDufeu  PDettling  MGraf  KRolfs  ARommelspacher  HSchmidt  LG Lack of allelic association of dopamine D1 and D2 (TaqIA) receptorgene polymorphisms with reduced dopaminergic sensitivity to alcoholism.  Alcohol Clin Exp Res. 1996;201109- 1113PubMedGoogle ScholarCrossref
16.
Lawford  BRYoung  RMRowell  JAGibson  JNFeeney  GFRitchie  TLSyndulko  KNoble  EP Association of the D2 dopamine receptor A1 allele with alcoholism:medical severity of alcoholism and type of controls.  Biol Psychiatry. 1997;41386- 393PubMedGoogle ScholarCrossref
17.
Turner  EEwing  JShilling  PSmith  TLIrwin  MSchuckit  MKelsoe  JR Lack of association between an RFLP near the D2 dopamine receptor geneand severe alcoholism.  Biol Psychiatry. 1992;31285- 290PubMedGoogle ScholarCrossref
18.
Parsian  ACloninger  CRZhang  ZH Functional variant in the DRD2 receptor promoter region and subtypesof alcoholism.  Am J Med Genet. 2000;96407- 411PubMedGoogle ScholarCrossref
19.
Ardlie  KGKruglyak  LSeielstad  M Patterns of linkage disequilibrium in the human genome.  Nat Rev Genet. 2002;3299- 309PubMedGoogle ScholarCrossref
20.
Nordborg  MTavare  S Linkage disequilibrium: what history has to tell us.  Trends Genet. 2002;1883- 90PubMedGoogle ScholarCrossref
21.
Gabriel  SBSchaffner  SFNguyen  HMoore  JMRoy  JBlumenstiel  BHiggins  JDeFelice  MLochner  AFaggart  MLiu-Cordero  SNRotimi  CAdeyemo  ACooper  RWard  RLander  ESDaly  MJAltshuler  D The structure of haplotype blocks in the human genome.  Science. 2002;2962225- 2228PubMedGoogle ScholarCrossref
22.
Wacholder  SRothman  NCaporaso  N Population stratification in epidemiologic studies of common geneticvariants and cancer: quantification of bias.  J Natl Cancer Inst. 2000;921151- 1158PubMedGoogle ScholarCrossref
23.
Pritchard  JKRosenberg  NA Use of unlinked genetic markers to detect population stratificationin association studies.  Am J Hum Genet. 1999;65220- 228PubMedGoogle ScholarCrossref
24.
Ardlie  KGLunetta  KLSeielstad  M Testing for population subdivision and association in four case-controlstudies.  Am J Hum Genet. 2002;71304- 311PubMedGoogle ScholarCrossref
25.
Xu  KLiu  XHNagarajan  SGu  XYGoldman  D Relationship of the delta-opioid receptor gene to heroin abuse in alarge Chinese case/control sample.  Am J Med Genet. 2002;11045- 50PubMedGoogle ScholarCrossref
26.
Shi  MMMyrand  SPBleavins  MRde la Iglesia  FA High throughput genotyping for the detection of a single nucleotidepolymorphism in NAD(P)H quinone oxidoreductase (DT diaphorase) using TaqManprobes.  Mol Pathol. PubMedGoogle Scholar
27.
Long  JCWilliams  RCUrbanek  M An E-M algorithm and testing strategy for multiple-locus haplotypes.  Am J Hum Genet. 1995;56799- 810PubMedGoogle Scholar
28.
Falush  DStephens  MPritchard  JK Inference of population structure using multilocus genotype data: linkedloci and correlated allele frequencies.  Genetics. 2003;1641567- 1587PubMedGoogle Scholar
29.
Smith  SSO'Hara  BFPersico  AMGorelick  DANewlin  DBVlahov  DSolomon  LPickens  RUhl  GR Genetic vulnerability to drug abuse: the D2 dopamine receptor Taq IB1 restriction fragment length polymorphism appears more frequently in polysubstanceabusers.  Arch Gen Psychiatry. 1992;49723- 727PubMedGoogle ScholarCrossref
30.
Kidd  KKMorar  BCastiglione  CMZhao  HPakstis  AJSpeed  WCBonne-Tamir  BLu  RBGoldman  DLee  CNam  YSGrandy  DKJenkins  TKidd  JR A global survey of haplotype frequencies and linkage disequilibriumat the DRD2 locus.  Hum Genet. 1998;103211- 227PubMedGoogle ScholarCrossref
31.
Devlin  BRoeder  KWasserman  L Genomic control, a new approach to genetic-based association studies.  Theor Popul Biol. 2001;60155- 166PubMedGoogle ScholarCrossref
32.
Cardon  LRPalmer  LJ Population stratification and spurious allelic association.  Lancet. 2003;361598- 604PubMedGoogle ScholarCrossref
33.
Drysdale  CMMcGraw  DWStack  CBStephens  JCJudson  RSNandabalan  KArnold  KRuano  GLiggett  SB Complex promoter and coding region β2-adrenergic receptor haplotypesalter receptor expression and predict in vivo responsiveness.  Proc Natl Acad Sci U S A. 2000;9710483- 10488PubMedGoogle ScholarCrossref
34.
Comings  DE Polygenic inheritance and micro/minisatellites.  Mol Psychiatry. 1998;321- 31PubMedGoogle ScholarCrossref
Original Article
June 2004

Association of Specific Haplotypes of D2 Dopamine ReceptorGene With Vulnerability to Heroin Dependence in 2 Distinct Populations

Author Affiliations

From the Laboratory of Neurogenetics, National Institute on AlcoholAbuse and Alcoholism, Rockville, Md (Drs Xu, Lipsky, and Goldman; Mss Ferro,Finch, Terry, and Taubman; and Mr Astor); Department of Psychiatry, Universityof Bonn, Bonn, Germany (Drs Lichtermann, Franke, Schwab, Wildenauer, and Maier);Department of Psychiatry, Sichuan University Medical School, Sichuan, China(Drs Liu and Cao); Laboratory of Population Genetics, National Cancer Institute,Bethesda, Md (Dr Hu); and Departamento de Genetica, Instituto de Biociencias,Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Dr Bau).

Arch Gen Psychiatry. 2004;61(6):597-606. doi:10.1001/archpsyc.61.6.597
Abstract

Context  Dopamine receptor–mediated pathways play critical roles in the mechanism of addiction. However, associations of the D2 dopamine receptor gene (DRD2) with substance abuse are controversial.

Objective  To determine whether susceptibility sites resided at DRD2.

Design  Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence.

Setting  Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China.

Patients  Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls).

Interventions  Genotyping for 10 SNPs by 5′-exonuclease fluorescence assays. The D′ value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm.

Main Outcome Measures  Genotype, allele, and haplotype frequencies were compared between cases and controls by χ2 tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations.

Results  A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5′ end to SNP10 site (TaqIA) located 10 kb distal to the 3′ end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 × 10−22; odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 × 10−11 for 8-SNP analysis). There was no evidence of population stratification in either population.

Conclusions  These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.

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