TY - JOUR
T1 - Association of specific haplotypes of D 2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations
AU - Xu, Ke
AU - Lichtermann, Dirk
AU - Lipsky, Robert H.
AU - Franke, Petra
AU - Liu, Xiehe
AU - Hu, Ying
AU - Cao, Liping
AU - Schwab, Sibylle G.
AU - Wildenauer, Dieter B.
AU - Bau, Claiton H.D.
AU - Ferro, Erica
AU - Astor, Will
AU - Finch, Thembi
AU - Terry, Jeanietta
AU - Taubman, Julie
AU - Maier, Wolfgang
AU - Goldman, David
PY - 2004/6/1
Y1 - 2004/6/1
N2 - Context: 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. 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 χ 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 × 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.
AB - Context: 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. 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 χ 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 × 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.
UR - http://www.scopus.com/inward/record.url?scp=2942525904&partnerID=8YFLogxK
U2 - 10.1001/archpsyc.61.6.597
DO - 10.1001/archpsyc.61.6.597
M3 - Article
C2 - 15184239
AN - SCOPUS:2942525904
SN - 0003-990X
VL - 61
SP - 597
EP - 606
JO - Archives of General Psychiatry
JF - Archives of General Psychiatry
IS - 6
ER -
