Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations.
BACKGROUND
Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D(2) dopamine receptor gene (DRD2) with substance abuse are controversial.


OBJECTIVE
To determine whether susceptibility sites resided at DRD2.


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


METHODS
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).


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


METHODS
Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) 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 x 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 x 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.
Xu
Ke
K
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA. ke@mail.nih.gov
Lichtermann
Dirk
D
Lipsky
Robert H
RH
Franke
Petra
P
Liu
Xiehe
X
Hu
Ying
Y
Cao
Liping
L
Schwab
Sibylle G
SG
Wildenauer
Dieter B
DB
Bau
Claiton H D
CH
Ferro
Erica
E
Astor
Will
W
Finch
Thembi
T
Terry
Jeanietta
J
Taubman
Julie
J
Maier
Wolfgang
W
Goldman
David
D
D000328:Adult; D001741:Black or African American / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D002681:China / Q000208:ethnology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000208:ethnology; D006239:Haplotypes / Q000235:genetics*; D006556:Heroin Dependence / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D044465:White People / Q000235:genetics*
D017448:Receptors, Dopamine D2