Important Variant Information for DRD2
Submitted by: Huijun Z. Ring, Ruhong Jiang, Caryn Lerman, Huaiyu Mi, Paul Thomas (The Pharmacogenetics of Nicotine Addiction and Treatment (PNAT) Research Consortium)
Reviewed by: Under Review
Submitted date: March 7, 2007
There are Four Important Variants for DRD2.
| Gene HGNC Name: | DRD2 |
|---|---|
| Variant Summary: | The -141C Ins/Del polymorphism is located in the promoter region of the DRD2 gene (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs1799732) and is found at an allele frequency of about 22% of the Japanese population. This allele is less common among Chinese and Caucasian populations (9%) [(PMID: 9713903]). Allele frequencies are known for a number of different populations, and of these, the deletion polymorphism is the most common allele in only the Yoruban sample (see Alfred (http://alfred.med.yale.edu/alfred/mvograph.asp?siteuid=SI000135J). Recent studies have shown that the -141 Ins/Del polymorphism of DRD2 may have a role in determining the response to antipsychotic drugs in schizophrenic inpatients. Suzuki et al examined a patient population of 49 schizophrenic inpatients, whose symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) test both before and three weeks following treatment with either bromperidol or nemonapride [11505224]. Patients who were homozygous for the Ins allele showed greater improvement in their anxiety-depression symptoms than did patients who were heterozygous at this position (there were no patients who were heterozygous for the Del allele in this study) [11505224]. Wu et al conducted a similar study in a larger population of 135 schizophrenic inpatients [15694263]. In this study, patients symptoms were evaluated both before and eight weeks following treatment with chloropromazine [15694263]. Wu et al had findings similar to that of Suzuki et al in that patients without the Del allele showed a higher degree of improvement of their overall BPRS scores than did patients who had at least one Del allele [15694263]. The therapeutic responses to DRD2 antagonists of patients with the -141C Ins/Del polymorphism clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) after 3 weeks of treatment with bromperidol or nemonapride. The patients without the Del allele showed a significant improvement in anxiety-depression symptoms than compared to those with the Del allele [PMID: 11505224]. These results suggest that the Del allele of the -141C Ins/Del DRD2 polymorphism is associated with a less favorable clinical outcome on antipsychotic therapy than the Ins allele in schizophrenic patients [15694263 11505224]. Subjects with -141C Ins allele in -141C Ins/Del polymorphism have a better response to dopamine antagonists [16045195]. Li and colleagues (2002) found a positive association between nasal inhalation of heroin use and the -141C Ins/Del DRD2 polymorphism in Chinese subjects [(PMID: 11920858]). Lerman et al suggest that the -141C Ins/Del polymorphism may influence whether bupropion or nicotine replacement therapy (NRT) would be more effective for tobacco dependence treatment [16123753]. The authors found that bupropion was more effective for patients who were homozygous for the Ins allele, whereas NRT appeared to be more helpful for patients who were homozygous for the Del allele [16123753]. |
| Key PubMed IDs: | PMID: 9713903, 11505224,15694263, 16045195, 11920858, 16123753. |
| Genomic Variant & GenBank ID: | 1690668 G > GC on NT_033899.7 (the inserted nucleotide is not present in this sequence) 23368089 G > [-] on NW_925173.1 (the inserted nucleotide is present in this sequence) |
| mRNA Variant & GenBank ID: | not applicable, this is a promoter variation |
| Protein Variant & GenBank ID: | not applicable, this is a promoter variation |
| dbSNP rs#: | rs1799732 |
| GoldenPath Position: | chr11: 112851462^chr11: 112851463 (hg18) (the inserted nucleotide is not present in this sequence) |
| Key Drugs/Substrates: | bromoperidol [PMID: 11505224] nemonapride [PMID: 11505224] chlorpromazine [PMID: 15694263] heroin [PMID: 11920858] bupropion [PMID: 16123753] |
| Key Phenotypes/Diseases: | Schizophrenia [PMID: 11505224, 15694263] Tobacco Use Disorder [PMID: 16123753] |
| Gene HGNC Name: | DRD2 |
|---|---|
| Variant Summary: | This variant is a SNP (C->G) in exon 7 that alters the codon 311 from the more common Ser to the less common Cys. The Cys311 variant has decreased affinity for dopamine [8824240]. The minor allele frequency (G allele) is 0.02 based on the 102 individuals of self-described heritage (African/African American, n=24, Caucasian, n=31, Hispanic, n=23, and Pacific Rim, n=24) (see dbSNP http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=1801028). From the same data set, the frequency of the G allele is higher in a self-described Pacific Rim population (0.043) than that in a Caucasian population (0.016). There is published evidence both supporting [7907680 7909081 8723039 11011590 12707934 16402354] and refuting [9650635] the association between Ser311Cys polymorphism of the DRD2 gene and schizophrenia (DSM-III-R). A possible link between the Cys allele of 311 Ser>Cys in DRD2 and schizophrenia was first reported in the mid 1990s [7907680 8723039 7909081], although Goldman et al found no correlation between carriers of Cys 311 and schizophrenia in a Native American population [9650635]. In 2003, Jonsson et al. examined the possible association of Ser311Cys and schizophrenia in control and schizophrenic populations, both of Swedish origin [12707934]. The schizophrenic patient population (n = 173) showed a higher allele frequency of Cys 311 than the contol population (n = 236) [12707934]. Interestingly, this association was detected only in male patients [12707934]. In a more recent study by Jonsson et al. [16402354], an analysis was conducted of several different studies which contained a total of 3,707 schizophrenia patients and 5,363 control subjects. The authors found that the Cys 311 allele had a significant effect under two different data models: the fixed-effect and the random-effect [16402354]. In the same study, the authors reported that Cys/Ser heterzygotes were at increased risk for schizophrenia as compared to the Ser/Ser homozygotes, but there was no increased risk detected between Cys/Ser heterozygotes and Cys/Cys homozygotes [16402354]. |
| Key PubMed IDs: | PMID: 8824240, 12707934, 16402354, 9650635 |
| Genomic Variant & GenBank ID: | 16845900 G>C on NT_033899.7 |
| mRNA Variant & GenBank ID: | 1097 C>G on NM_000795.2 1010 C>G on NM_016574.2 |
| Protein Variant & GenBank ID: | 311 Ser> Cys on NP_000786 (long isoform) 282 Ser>Cys on NP_057658 (short isoform) |
| dbSNP rs#: | rs1801028 |
| GoldenPath Position: | chr11: 112788694 (hg18) |
| Key Drugs/Substrates: | |
| Key Phenotypes/Diseases: | Schizophrenia [PMID: 12707934, 16402354, 9650635] |
| Gene HGNC Name: | DRD2 |
|---|---|
| Variant Summary: | The DRD2 gene Taq1A (C32806T) polymorphism has an overall minor allele frequency of 0.315. The frequency of the minor T allele differs among ethnic populations. It occurs in about 22% of the European Caucasian population and is more frequent in Asian and African populations (42%) (see dbSNP http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=1800497). Swan GE (2005) reported that the DRD2 gene Taq1A (C32806T) polymorphism is associated with 12-month smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling in women (PMID: 15492764). Shafer and colleagues (2001) found subjects that were heterozygous for this polymorphism showed a greater improvement in their positive symptoms as assessed by the Positive and Negative Syndrome SCALE while being treated with the dopamine antagonist haloperidol, an antipsychotic drug with greater D2 affinity than clozapine [11329406]. A study (2000) of 25 Japanese schizophrenic inpatients suggested that female patients with the A1 allele showed a greater prolactin response to nemonapride. These subjects may be at high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia [10823405].` |
| Key PubMed IDs: | PMID: 15492764, 11329406, 10823405 |
| Genomic Variant & GenBank ID: | 16833244 G>A on NT_033899.7 [Taq1A (C32806T) polymorphism] |
| mRNA Variant & GenBank ID: | There are no changes to the DRD2 mRNA, but this variation causes a change in the ANKK1 mRNA |
| Protein Variant & GenBank ID: | There are no changes to the DRD2 protein, but this variation causes a nonsynonymous change in ANKK1. |
| dbSNP rs#: | rs1800497 |
| GoldenPath Position: | chr11:112776038 (hg18) |
| Key Drugs/Substrates: | bupropion [PMID: 15492764] haloperidol [PMID: 11329406] nemonapride [PMID: 10823405 |
| Key Phenotypes/Diseases: | Tobacco Use Disorder [PMID: 15492764] Schizophrenia [PMID: 10823405, 11329406] |
| Gene HGNC Name: | DRD2 |
|---|---|
| Variant Summary: | This variant is a coding SNP (C->T) located in exon 7. The minor allele (T) frequency varies among geographic groups ranging from 7-12% in African and Asian populations to about 48% in Caucasian populations. Overall, it occurs with a frequency of 26% in human populations (see dbSNP http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=6277). Lawford et al conducted a study that examined the role of the C957T polymorphism in DRD2 in determining mRNA levels of DRD2 [15567074]. The authors found that the T allele led to a decrease in mRNA levels and stability whereas the C allele was not found to be associated with any mRNA changes, which led to a relative increase in the expression of DRD2 in carriers of the C allele [15567074]. Lawford et al also examined the frequencies of the C and T alleles in a schizophrenic (n=153), and control (n=148) population and found that there was an association between the C/C genotype and schizophrenia [15567074]. The authors also determined both a population attributable risk (24%), and an attributable risk among the schizophrenic population (42%) for the C957T polymorphism. These results suggest that an increased expression of D2 receptors resulting from the increased stability of the C allele may be a contributing factor to certain forms of schizophrenia [15567074]. Lerman et al reported (2006) that the C957T polymorphism in DRD2 was associated (p=0.03) with abstinence from tobacco at the completion of nicotine replacement therapy(NRT) [16123753]. |
| Key PubMed IDs: | PMID: 15567074, 16123753. |
| Genomic Variant & GenBank ID: | 16845875 G>A on NT_033899.7 |
| mRNA Variant & GenBank ID: | 1122 C>T on NM_000795 1035 C>T on NM_016574 |
| Protein Variant & GenBank ID: | 319 Pro 319 >Pro on NP_000786 (long isoform) 290 Pro 290 >Pro on NP_057658 (short isoform) |
| dbSNP rs#: | rs6277 |
| GoldenPath Position: | chr11: 112788669 (hg18) |
| Key Drugs/Substrates: | bupropion [PMID: 16123753] |
| Key Phenotypes/Diseases: | Schizophrenia [PMID: 15567074] Tobacco Use Disorder [PMID: 16123753] |