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Association of specific haplotypes of D 2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations

Journal Article


Abstract


  • 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 �� 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.

Publication Date


  • 2004

Citation


  • Xu, K., Lichtermann, D., Lipsky, R. H., Franke, P., Liu, X., Hu, Y., . . . Goldman, D. (2004). Association of specific haplotypes of D 2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Archives of General Psychiatry, 61(6), 597-606. doi:10.1001/archpsyc.61.6.597

Scopus Eid


  • 2-s2.0-2942525904

Web Of Science Accession Number


Start Page


  • 597

End Page


  • 606

Volume


  • 61

Issue


  • 6

Place Of Publication


Abstract


  • 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 �� 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.

Publication Date


  • 2004

Citation


  • Xu, K., Lichtermann, D., Lipsky, R. H., Franke, P., Liu, X., Hu, Y., . . . Goldman, D. (2004). Association of specific haplotypes of D 2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Archives of General Psychiatry, 61(6), 597-606. doi:10.1001/archpsyc.61.6.597

Scopus Eid


  • 2-s2.0-2942525904

Web Of Science Accession Number


Start Page


  • 597

End Page


  • 606

Volume


  • 61

Issue


  • 6

Place Of Publication