1Mol. Psychiatry 2000 Jul 5: 418-24
PMID10889553
TitleDopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia.
AbstractThe dopamine D4 receptor (DRD4) may play a role in the pathogenesis of neuropsychiatric disease and in the action of dopaminergic drugs. The 48-bp repeat polymorphism (48-bp VNTR) coding for a 16-amino acid segment in the third cytoplasmatic loop of the DRD4 was studied as a predictor of the therapeutic response to antipsychotics and as susceptibility factor for schizophrenia. We included 638 in-patients with acute schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses, as well as two reference groups: one with 278 in-patients with non-psychiatric diseases, and one with 474 healthy volunteers. Catatonic patients (DSM-IV 295.2) more frequently carried the DRD4 D4.2 and D4.3 allele than did all other schizophrenic cases (P < 0.001; OR: 2.7; CI: 1.5-4.9) and controls (P < 0.004; OR: 2.3; CI: 1.3-4.2). We found no significant difference in the DRD4 allele or in genotype frequencies in our comparison of all schizophrenic patients and controls. The subgroups with affected family members, and the subgroups with early or late onset of disease, also did not differ from the controls in DRD4 allele frequencies. The 48-bp VNTR was not a predictor for therapeutic outcome measured by the positive and negative symptoms scale. A total of 1390 subjects showed between 1 and 10 repeats (D4. 1 and D4.10), with 25 different genotypes. These data exclude a major role of DRD4 48-bp VNTR in response to antipsychotic therapy and as susceptibility factor for schizophrenia, but catatonic schizophrenia may be associated with the D4.2 and D4.3 alleles.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
2Mol. Psychiatry 2000 Jul 5: 418-24
PMID10889553
TitleDopamine D4 receptor 48-bp repeat polymorphism: no association with response to antipsychotic treatment, but association with catatonic schizophrenia.
AbstractThe dopamine D4 receptor (DRD4) may play a role in the pathogenesis of neuropsychiatric disease and in the action of dopaminergic drugs. The 48-bp repeat polymorphism (48-bp VNTR) coding for a 16-amino acid segment in the third cytoplasmatic loop of the DRD4 was studied as a predictor of the therapeutic response to antipsychotics and as susceptibility factor for schizophrenia. We included 638 in-patients with acute schizophrenic, schizoaffective (mainly schizophrenic), and other nonaffective psychoses, as well as two reference groups: one with 278 in-patients with non-psychiatric diseases, and one with 474 healthy volunteers. Catatonic patients (DSM-IV 295.2) more frequently carried the DRD4 D4.2 and D4.3 allele than did all other schizophrenic cases (P < 0.001; OR: 2.7; CI: 1.5-4.9) and controls (P < 0.004; OR: 2.3; CI: 1.3-4.2). We found no significant difference in the DRD4 allele or in genotype frequencies in our comparison of all schizophrenic patients and controls. The subgroups with affected family members, and the subgroups with early or late onset of disease, also did not differ from the controls in DRD4 allele frequencies. The 48-bp VNTR was not a predictor for therapeutic outcome measured by the positive and negative symptoms scale. A total of 1390 subjects showed between 1 and 10 repeats (D4. 1 and D4.10), with 25 different genotypes. These data exclude a major role of DRD4 48-bp VNTR in response to antipsychotic therapy and as susceptibility factor for schizophrenia, but catatonic schizophrenia may be associated with the D4.2 and D4.3 alleles.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
3Mol. Psychiatry 2001 Mar 6: 168-72
PMID11317218
TitleAn in-frame deletion in the alpha(2C) adrenergic receptor is common in African--Americans.
Abstractalpha(2) adrenergic receptors are activated by adrenaline and noradrenaline, and three subtypes (ie, A, B, C) have differential affinities for antagonists and medications. The alpha(2c) adrenergic receptor (ADRA2C), located on chromosome 4p16.3, is a candidate gene for schizophrenia because it binds clozapine, an atypical neuroleptic useful for treatment-resistant schizophrenia. In addition, ADRA2C binds clonidine which is prescribed for three psychiatric diseases. This report communicates the findings of the genetic scanning of this gene of very tough GC content. The complete coding sequences and splice junctions were scanned with [DOVAM]-S in 104 schizophrenics, and pilot probes of patients with alcoholism (41 patients), cocaine abuse (25 patients), puerperal psychosis (30 patients), attention deficient/hyperactivity disorder (25 patients) and autism (25 patients). Six sequence variants were found, including five silent polymorphisms (allele frequencies 0.6--25%) and an in-frame deletion of a homologous repeat at nucleotides 967--978 (ie, TIDRU(1)). Genotyping of the normal two repeat unit of the Third Intracytoplasmic Domain Repeat Unit (TIDRU(2)) and the deleted variant (TIDRU(1)) revealed that TIDRU(1) had allelic frequencies of 39% (11/28) and 3.5% (6/172) in African-American and Caucasian schizophrenics, respectively, and it occurred with equal frequency in controls (44%, 31/70 and 3.0%, 6/198). TIDRU(1) occurs at a location similar to the third intracytoplasmic 48-nucleotide repeat unit in the DRD4 that is associated with ADHD. Although these data do not suggest an association of TIDRU(1) with schizophrenia, additional studies are needed to see whether TIDRU(1) confers a clinical phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
4Zhonghua Yi Xue Za Zhi 2001 Aug 81: 995-8
PMID11718085
Title[Schizophrenia and dopamine D4 gene polymorphism in Chinese population: association analysis].
AbstractTo investigate the association of the 48 bp variable number tandem repeat (VNTR) polymorphism in the dopamine D4 receptor (DRD4) gene exon III with schizophrenia in Chinese Han population.
Case-control association study was adopted to analyze the association between the 48 bp VNTR polymorphism of DRD4 gene exon III in 510 DSM-IV schizophrenics and 171 psychiatrically normal controls.
(1) The DRD4 gene 48 bp VNTR polymorphism was manifested as 2-7 repeats, with the 4 repeats the most common (78.6% in schizophrenics and 76.9% in controls respectively). The frequency of 2 repeats was 16.2% and 19.3% in the schizophrenics and controls respectively. (2) The genotypic frequency was statistically significantly different between the schizophrenics and the controls. The genotypic frequency of short tandem repeats (2/2 and 2/3 genotype) was lower in patients (3.3%) than in controls (10.5%) (chi 2 = 14.88, df = 2, P = 0.00). (3) the frequency of the genotype with 4-repeat allele in patients was higher (95.9%) than in controls (88.3%) (chi 2 = 13.00, df = 1, P = 0.000).
The most common allele in Chinese schizophrenics was 4 repeats in the 48 bp VNTR polymorphism of DRD4 gene exon III. The repeat number of 48 bp is probably associated with schizophrenia. Lack of 2-3 repeats or excess of genotype with 4-repeat allele may be associated with increased vulnerability to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
5Am. J. Med. Genet. 2001 Aug 105: 525-8
PMID11496369
TitleNo association between a promoter dopamine D(4) receptor gene variant and schizophrenia.
AbstractThe dopamine D(4) receptor has been implicated in the pathogenesis of schizophrenia. An association between a putative functional promoter polymorphism (-521C/T) in the dopamine D(4) receptor gene (DRD4) and schizophrenia was recently reported. In the present study, patients with schizophrenia (n = 132) and control subjects (n = 388) were analyzed with respect to the DRD4 - 521C/T polymorphism. No significant case control differences emerged. The present results do not support a major role for DRD4 in the etiology of schizophrenia among Caucasians from Sweden.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
6Electrophoresis 2001 Apr 22: 1102-5
PMID11358133
TitleGenotyping the -521C/T functional polymorphism in the promoter region of dopamine D4 receptor (DRD4) gene.
AbstractThe -521C/Tsingle nucleotide polymorphism (SNP) in the promoter region of the dopamine D4 receptor gene (DRD4) has recently been detected in oriental (Japanese) individuals and related to novelty seeking and schizophrenia. Here, we report the analysis of the -521C/T polymorphism in a Caucasian (Hungarian) population using two independent genotyping methods. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure utilized the Fspl restriction site around the -521 position. An additional, nonpolymorphic cleavage site was also included into the amplified region to serve as an internal standard for verifying the completion of the digestion. As another independent method, a tetraprimer system for single-tube allele-specific PCR (SAS-PCR) was developed to generate -521C and -521T specific PCR products with different fragment sizes. Consequently, genotyping with SAS-PCR is based on the gel-electrophoretic separation of the allele-specific double-stranded DNA (dsDNA) fragments. 119 healthy Hungarian individuals were genotyped for -521C/T polymorphism of the dopamine D4 promoter region, using both methods. Similar allele frequencies were found (-521C allele: 0.43; -521T allele: 0.57) as reported earlier for the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
7J. Hum. Genet. 2001 -1 46: 26-31
PMID11289715
TitleAssociation analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits.
AbstractThe human dopamine D4 receptor (DRD4) is of major interest in molccular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (-768G>A in the negative modulator region; -521C>T, -376C >T, and -291C>T in the cell type-specific promoter region; and -616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The -768G>A polymorphism was significantly associated with reward dependence (P= 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
8Am. J. Med. Genet. 2001 Apr 105: 283-90
PMID11353451
TitleDRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects.
AbstractWe previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample of 1,264 patients were evaluated using the OPCRIT checklist and differences of symptomatology factor scores among genetic variants were assessed using one-way analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars, schizophrenics, delusionals, and psychotic NOS were not significantly different from controls; major depressives showed a trend toward an excess of DRD4*Short and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the whole subsample of 1,264 subjects showed a significant difference on delusion factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long containing variants associated with severe symptomatology. The analysis in the replication subjects only (n = 803) showed a trend in the same direction, though not reaching the significance level. This analysis in an enlarged sample suggests that DRD4*Long alleles exert a small but significant influence on the delusional symptomatology in subjects affected by major psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
9Mol. Psychiatry 2001 Mar 6: 168-72
PMID11317218
TitleAn in-frame deletion in the alpha(2C) adrenergic receptor is common in African--Americans.
Abstractalpha(2) adrenergic receptors are activated by adrenaline and noradrenaline, and three subtypes (ie, A, B, C) have differential affinities for antagonists and medications. The alpha(2c) adrenergic receptor (ADRA2C), located on chromosome 4p16.3, is a candidate gene for schizophrenia because it binds clozapine, an atypical neuroleptic useful for treatment-resistant schizophrenia. In addition, ADRA2C binds clonidine which is prescribed for three psychiatric diseases. This report communicates the findings of the genetic scanning of this gene of very tough GC content. The complete coding sequences and splice junctions were scanned with [DOVAM]-S in 104 schizophrenics, and pilot probes of patients with alcoholism (41 patients), cocaine abuse (25 patients), puerperal psychosis (30 patients), attention deficient/hyperactivity disorder (25 patients) and autism (25 patients). Six sequence variants were found, including five silent polymorphisms (allele frequencies 0.6--25%) and an in-frame deletion of a homologous repeat at nucleotides 967--978 (ie, TIDRU(1)). Genotyping of the normal two repeat unit of the Third Intracytoplasmic Domain Repeat Unit (TIDRU(2)) and the deleted variant (TIDRU(1)) revealed that TIDRU(1) had allelic frequencies of 39% (11/28) and 3.5% (6/172) in African-American and Caucasian schizophrenics, respectively, and it occurred with equal frequency in controls (44%, 31/70 and 3.0%, 6/198). TIDRU(1) occurs at a location similar to the third intracytoplasmic 48-nucleotide repeat unit in the DRD4 that is associated with ADHD. Although these data do not suggest an association of TIDRU(1) with schizophrenia, additional studies are needed to see whether TIDRU(1) confers a clinical phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
10Zhonghua Yi Xue Za Zhi 2001 Aug 81: 995-8
PMID11718085
Title[Schizophrenia and dopamine D4 gene polymorphism in Chinese population: association analysis].
AbstractTo investigate the association of the 48 bp variable number tandem repeat (VNTR) polymorphism in the dopamine D4 receptor (DRD4) gene exon III with schizophrenia in Chinese Han population.
Case-control association study was adopted to analyze the association between the 48 bp VNTR polymorphism of DRD4 gene exon III in 510 DSM-IV schizophrenics and 171 psychiatrically normal controls.
(1) The DRD4 gene 48 bp VNTR polymorphism was manifested as 2-7 repeats, with the 4 repeats the most common (78.6% in schizophrenics and 76.9% in controls respectively). The frequency of 2 repeats was 16.2% and 19.3% in the schizophrenics and controls respectively. (2) The genotypic frequency was statistically significantly different between the schizophrenics and the controls. The genotypic frequency of short tandem repeats (2/2 and 2/3 genotype) was lower in patients (3.3%) than in controls (10.5%) (chi 2 = 14.88, df = 2, P = 0.00). (3) the frequency of the genotype with 4-repeat allele in patients was higher (95.9%) than in controls (88.3%) (chi 2 = 13.00, df = 1, P = 0.000).
The most common allele in Chinese schizophrenics was 4 repeats in the 48 bp VNTR polymorphism of DRD4 gene exon III. The repeat number of 48 bp is probably associated with schizophrenia. Lack of 2-3 repeats or excess of genotype with 4-repeat allele may be associated with increased vulnerability to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
11Am. J. Med. Genet. 2001 Apr 105: 283-90
PMID11353451
TitleDRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects.
AbstractWe previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample of 1,264 patients were evaluated using the OPCRIT checklist and differences of symptomatology factor scores among genetic variants were assessed using one-way analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars, schizophrenics, delusionals, and psychotic NOS were not significantly different from controls; major depressives showed a trend toward an excess of DRD4*Short and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the whole subsample of 1,264 subjects showed a significant difference on delusion factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long containing variants associated with severe symptomatology. The analysis in the replication subjects only (n = 803) showed a trend in the same direction, though not reaching the significance level. This analysis in an enlarged sample suggests that DRD4*Long alleles exert a small but significant influence on the delusional symptomatology in subjects affected by major psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
12J. Hum. Genet. 2001 -1 46: 26-31
PMID11289715
TitleAssociation analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits.
AbstractThe human dopamine D4 receptor (DRD4) is of major interest in molccular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (-768G>A in the negative modulator region; -521C>T, -376C >T, and -291C>T in the cell type-specific promoter region; and -616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The -768G>A polymorphism was significantly associated with reward dependence (P= 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
13Schizophr. Res. 2002 Oct 57: 239-45
PMID12223255
TitleEthnic heterogeneity in allele variation in the DRD4 gene in schizophrenia.
AbstractThe goal of the present study was to use a meta-analysis on previous studies plus our own unpublished data to confirm and extend findings which indicate that the variation in the dopamine D4 receptor (DRD4) gene is best represented by a mixture of two different ethnic groups. The genotype distribution was divided into either a long or short form using a mixture analysis of normal controls of different ethnic origins under the assumption that there is a single major gene. The meta-analysis was based on the data from 19 independent samples, 18 association studies, and from our own unpublished data, including a total of 1431 schizophrenic patients (sporadic cases 1309, familial cases 122) and 1439 controls. No significant genotype differences were noted between patients and controls for the whole sample. However, reorganization of the studies into different groups by the geographical origin of samples revealed significant ethnic heterogeneity. In addition, there was a significant association between the long form of DRD4 gene and schizophrenia in Caucasians, especially those with familial schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
14Schizophr. Res. 2002 Oct 57: 239-45
PMID12223255
TitleEthnic heterogeneity in allele variation in the DRD4 gene in schizophrenia.
AbstractThe goal of the present study was to use a meta-analysis on previous studies plus our own unpublished data to confirm and extend findings which indicate that the variation in the dopamine D4 receptor (DRD4) gene is best represented by a mixture of two different ethnic groups. The genotype distribution was divided into either a long or short form using a mixture analysis of normal controls of different ethnic origins under the assumption that there is a single major gene. The meta-analysis was based on the data from 19 independent samples, 18 association studies, and from our own unpublished data, including a total of 1431 schizophrenic patients (sporadic cases 1309, familial cases 122) and 1439 controls. No significant genotype differences were noted between patients and controls for the whole sample. However, reorganization of the studies into different groups by the geographical origin of samples revealed significant ethnic heterogeneity. In addition, there was a significant association between the long form of DRD4 gene and schizophrenia in Caucasians, especially those with familial schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
15Schizophr. Res. 2003 May 61: 111-9
PMID12648742
TitleDopamine D4 receptor gene (DRD4) variants and schizophrenia: meta-analyses.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
16Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Feb 20: 69-71
PMID12579508
Title[Associations between six functional genes and schizophrenia].
AbstractTo assess the associations between schizophrenia and six functional genes: dopamine D2 receptor gene (DRD2), dopamine D4 receptor gene (DRD4), 5-hydroxytryptamine 2A receptor gene (5-HT2A), 5-HT6 receptor gene (5-HT6), catechol-O-methyltransferase gene (COMT) and dopamine transporter gene (DAT1).
With the techniques of Amp-RFLP and Amp-FLP, association analysis was made between schizophrenia and the six genes in 67 schizophrenic patients from Chinese Han population.
(1) Neither genotypes nor alleles of DRD2, 5-HT2A, 5-HT6 and COMT gene showed significant differences between patients and controls (P>0.05). (2) Six repeats (6R) in DRD4 gene, the allele of 480 bp and the genotype of 480/520 in DAT1 gene were found to be of significant differences between the two groups (P<0.05). (3) Only one negative association was observed between the 480 bp allele of DAT1 gene and schizophrenia (OR=0.441, 95% CI:0.202-0.963, Z=2.05, P<0.05).
The 480 bp allele of DAT1 gene is negatively associated with schizophrenia in Chinese Han population, which stands for the dopamine hypothesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
17Pharmacogenomics J. 2003 -1 3: 277-83
PMID14583797
TitleAssociation of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia.
AbstractTardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
18Schizophr. Res. 2003 Dec 65: 9-14
PMID14623368
TitleAssociation analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene in schizophrenia.
AbstractSeveral studies have suggested that the transcriptional activity of the DRD4 gene may exert an important role in susceptibility to schizophrenia. To address this issue, we studied the association of schizophrenia and polymorphisms including -616C>G, -603T>del, -602G>del, 600G>C, -521C>T, -376C>T and a 120 bp tandem duplication polymorphism (120 bp repeat) in 1.2 kb upstream from the initiation codon in the promoter region of the DRD4 gene with 210 schizophrenic cases and 206 healthy controls. The results showed a significant excess of allele L of the 120 bp repeat in the schizophrenic patients compared to the controls (X(2)=8.585, df=1, P=0.003, OR=1.546, 95% CI=1.154-2.070). No significant difference was detected in the frequencies of genotype and allele of six other polymorphisms between the two groups. However, haplotypic distribution of 120 bp repeat, -616C>G, -602G>del, -521C>T and -376C>T was significantly different between case and control groups (P=0.005). This might cause the alteration of the transcriptional regulation of the DRD4 gene, as the consensus sequences of binding sites for several known transcription factors are involved in this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
19Biol. Psychiatry 2003 Sep 54: 629-35
PMID13129658
TitleSchizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis.
AbstractThe gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies.
We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2,300 cases and 2,100 controls from 14-16 studies.
The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele.
Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
20Eur Neuropsychopharmacol 2003 May 13: 183-5
PMID12729944
TitleDRD4 exon III polymorphism and response to risperidone in Israeli adolescents with schizophrenia: a pilot pharmacogenetic study.
AbstractThis study examined the possible association between the polymorphism in the dopamine receptor DRD4 gene and response to risperidone among 24 Israeli Jewish adolescent inpatients with first-episode schizophrenia. Response was categorically determined by a change of >40% on the Brief Psychiatric Rating Scale (BPRS). No significant association was found between the DRD4 genotype and clinical response, although carriers of <7 repeat alleles demonstrated higher response rate (10/20 vs. 0/4, P=0.11). Studies in larger groups of adolescent schizophrenia patients are warranted to clarify the possible association between DRD4 exon III repeat alleles and the response to risperidone.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
21Psychiatry Res 2003 Jul 119: 99-111
PMID12860364
TitleGene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms.
AbstractGenetic and environmental factors, as well as their interactions, are likely to be involved in psychiatric disorders. Considerable progress has been made in association and linkage studies with various candidate genes, at times with conflicting or ambiguous results. An environmental factor that has persistently shown associations with several psychiatric and neurological disorders is the season of birth. If it is the interaction of a specific gene allele with a specific season of birth that constitutes an increased (or decreased) risk for a disorder, then the individuals with this disorder are likely to have a season of birth variation in this gene allele. We investigated the variations in TPH, 5-HTTLPR and DRD4 gene polymorphisms according to seasonality of birth in 954 patients with unipolar affective disorder, bipolar affective disorder, and schizophrenia, respectively, and in 395 controls. We first analyzed season of birth variations in the gene alleles with one cycle or two cycles per year, and then compared specified birth seasons with each other. We found season of birth variations in these gene alleles that were different for different psychiatric disorders. Significant differences between cases and controls could be obtained when restricting the analysis within certain birth seasons but not within others. Our results thus suggest an interaction between the seasons of birth and the expression of the candidate genes, and that season of birth is a confounding variable when investigating the role of the candidate genes in susceptibility to psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
22Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Feb 20: 69-71
PMID12579508
Title[Associations between six functional genes and schizophrenia].
AbstractTo assess the associations between schizophrenia and six functional genes: dopamine D2 receptor gene (DRD2), dopamine D4 receptor gene (DRD4), 5-hydroxytryptamine 2A receptor gene (5-HT2A), 5-HT6 receptor gene (5-HT6), catechol-O-methyltransferase gene (COMT) and dopamine transporter gene (DAT1).
With the techniques of Amp-RFLP and Amp-FLP, association analysis was made between schizophrenia and the six genes in 67 schizophrenic patients from Chinese Han population.
(1) Neither genotypes nor alleles of DRD2, 5-HT2A, 5-HT6 and COMT gene showed significant differences between patients and controls (P>0.05). (2) Six repeats (6R) in DRD4 gene, the allele of 480 bp and the genotype of 480/520 in DAT1 gene were found to be of significant differences between the two groups (P<0.05). (3) Only one negative association was observed between the 480 bp allele of DAT1 gene and schizophrenia (OR=0.441, 95% CI:0.202-0.963, Z=2.05, P<0.05).
The 480 bp allele of DAT1 gene is negatively associated with schizophrenia in Chinese Han population, which stands for the dopamine hypothesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
23Pharmacogenomics J. 2003 -1 3: 277-83
PMID14583797
TitleAssociation of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia.
AbstractTardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
24Schizophr. Res. 2003 Dec 65: 9-14
PMID14623368
TitleAssociation analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene in schizophrenia.
AbstractSeveral studies have suggested that the transcriptional activity of the DRD4 gene may exert an important role in susceptibility to schizophrenia. To address this issue, we studied the association of schizophrenia and polymorphisms including -616C>G, -603T>del, -602G>del, 600G>C, -521C>T, -376C>T and a 120 bp tandem duplication polymorphism (120 bp repeat) in 1.2 kb upstream from the initiation codon in the promoter region of the DRD4 gene with 210 schizophrenic cases and 206 healthy controls. The results showed a significant excess of allele L of the 120 bp repeat in the schizophrenic patients compared to the controls (X(2)=8.585, df=1, P=0.003, OR=1.546, 95% CI=1.154-2.070). No significant difference was detected in the frequencies of genotype and allele of six other polymorphisms between the two groups. However, haplotypic distribution of 120 bp repeat, -616C>G, -602G>del, -521C>T and -376C>T was significantly different between case and control groups (P=0.005). This might cause the alteration of the transcriptional regulation of the DRD4 gene, as the consensus sequences of binding sites for several known transcription factors are involved in this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
25Biol. Psychiatry 2003 Sep 54: 629-35
PMID13129658
TitleSchizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis.
AbstractThe gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies.
We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2,300 cases and 2,100 controls from 14-16 studies.
The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele.
Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
26Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 69-78
PMID14755448
TitleClinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study.
Abstractschizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
27Int. J. Neuropsychopharmacol. 2004 Dec 7: 489-93
PMID15383158
TitleTardive dyskinesia and DRD2, DRD3, DRD4, 5-HT2A variants in schizophrenia: an association study with repeated assessment.
AbstractWe performed an association study between four candidate genes, DRD2, DRD3, DRD4 and 5-HT2A for the presence of tardive dyskinesia (TD) on 84 patients with residual schizophrenia. The sample was evaluated again for the presence of TD after an interval of 3 years. The first group did not exhibit TD in either observation (n=34) while in the second group of patients exhibited TD in at least one of the observations (n=20+18). The clinical and socio-demographic characteristics were not significantly different between the two groups; the genetic analysis revealed a significant correlation between the C/C genotype of 5-HT2A and TD (p=0.017). An association trend was observed between the 'short' variant of DRD4 and TD (p=0.022). We did not observe any significant association for the DRD2 and DRD3 polymorphisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
28Biol. Psychiatry 2004 Nov 56: 691-7
PMID15522254
TitleFunctional effects of a tandem duplication polymorphism in the 5'flanking region of the DRD4 gene.
AbstractSeveral polymorphisms have been identified in the 5'flanking region of the human dopamine D(4) receptor gene (DRD4), including a tandem duplication polymorphism. This comprises a 120-base-pair repeat sequence that is known to have different allele frequencies in various populations around the world. Furthermore, various studies have revealed evidence of linkage to attention-deficit/hyperactivity disorder and association with schizophrenia and methamphetamine abuse. The location of the polymorphism in the 5'regulatory region of the DRD4 gene and the fact that it consists of potential transcription factor binding sites suggest that it might confer differential transcriptional activity of the alleles.
We investigated the functional effects of this gene variant with transient transfection methods in four human cell lines and then assessed transcriptional activity with luciferase reporter gene assays.
The longer allele has lower transcriptional activity than the shorter allele in SK-N-MC, SH-SY5Y, HEK293, and HeLa cell lines.
This evidence suggests that the duplication might have a role in regulating the expression of the DRD4 gene and provides an understanding of the biological mechanisms underlying the etiology of neuropsychiatric disorders such as ADHD, schizophrenia, and metamphetamine abuse.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
29Neurosci. Lett. 2004 Sep 368: 269-73
PMID15364409
TitleDRD4 exon 3 variants are not associated with symptomatology of major psychoses in a German population.
AbstractWe previously reported an association of DRD4 exon 3 long alleles with delusional symptomatology, independently from psychiatric diagnoses [Am. J. Med. Genet. 105 (2001) 283; Psychiatry Res. 80 (1998) 129]. The aim of this investigation was to replicate these results in an independent sample from Germany. We studied 394 subjects, affected by bipolar disorder (n = 32), schizoaffective disorder (n = 45), and schizophrenia (n = 317). All affected subjects were evaluated using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. DRD4 variants were not associated with symptomatology of major psychosis. Our present results, obtained in an independent German sample, did not confirm the association between DRD4 variants and delusional symptomatology. However it should be considered that the original sample included a much higher rate of mood disorders and this could partially explain the discrepancy.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
30Neurosci. Lett. 2004 Aug 366: 282-6
PMID15288435
TitleGene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism.
AbstractRecently, an interaction between season of birth and the expression of candidate genes has been suggested. Season of birth variations in tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR) and the dopamine D4 receptor (DRD4) gene polymorphisms are different for affective disorders and schizophrenia. The DRD4 gene has been postulated as a candidate gene for attention-deficit-hyperactivity disorder (ADHD), equivalent to hyperkinetic disorder (HD). The seven-repeat long variant of this gene (DRD4*7) in comparison to the short repeat variants of the DRD4 gene polymorphism, has been found to be associated with ADHD. A seasonal pattern of birth has also been proposed for different subtypes of ADHD. Therefore, in a subgroup of children with HD and conduct disorder (CD) and in healthy controls, we investigated a possible association between the DRD4*7 allele and HD + CD in association with the season of birth. Supporting this hypothesis, we found an interaction between the seasons of birth and the expression of the DRD4 candidate gene in children with HD + CD as well as in controls, which differ significantly from each other. Depending on the season of birth, children carrying the DRD4*7R allele showed different relative risks for developing HD + CD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
31Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 20-4
PMID14755438
TitleNo evidence of association or linkage disequilibrium between polymorphisms in the 5' upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population.
AbstractAlterations in dopaminergic system have been implicated in the pathophysiology of this disease for many years, and this study was performed to assess the possible involvement of the dopamine D4 receptor (DRD4) gene polymorphisms either in the 5' upstream or in the coding regions, in the etiology of schizophrenia. The approach included an association study with 90 Portuguese trios by doing the analysis of the individual alleles and the haplotypes. For the polymorphisms in the 5' upstream region (-C616G and -C521T) and in the coding region (48 bp repeat) of the DRD4 gene, negative results were obtained with both haplotype relative risk (HRR) and transmission disequilibrium test (TDT), as well as transmit. These data suggest that polymorphisms (-C616G, -C521T, and 48 bp repeat) at the DRD4 gene do not have a minor effect in the susceptibility to schizophrenia in our sample.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
32Proc. Natl. Acad. Sci. U.S.A. 2005 Mar 102: 3513-8
PMID15716360
TitleDopamine supersensitivity correlates with D2High states, implying many paths to psychosis.
AbstractDopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), DRD4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
33J Neural Transm (Vienna) 2005 Nov 112: 1575-82
PMID15785860
TitleAn association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia.
AbstractDopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
34Am J Pharmacogenomics 2005 -1 5: 149-60
PMID15952869
TitleGenetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope.
AbstractNo specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
35Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 35-41
PMID16281377
Title[A study of some genes related to serotoninergic and dopaminergic systems and auditory evoked-potentials (P300) in patients with schizophrenia and spectrum disorders and their first-degree relatives].
AbstractThe changes of P300 parameters (lower amplitude and increased latency) are thought to be the most prominent phenomena of schizophrenia. A role of gene polymorphism in P300 generation was supported by several associative studies in psychiatrically well subjects and patients with mental disorders. We studied P300 parameters and the following polymorphisms: T102C for the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR for the serotonin transporter gene, -809G/A, -616G/C N -52C/T SNPs in the promoter region of the dopamine D4 receptor (DRD4) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) in 74 patients with schizophrenia and spectrum disorders and 71 their first-degree relatives. No association was found between serotonergic system genes and P300. The -809G/A DRD4 gene polymorphism was related to amplitude in all frontal leads (p=0,01) in patients. In relatives, an association was observed between -521C/T DRD4 variants and latency (p=0,005) as well as between the COMT gene polymorphism and P300 amplitude (p=0,004) at the central lead. Thus, the genes involved in dopaminergic system play a role in P300 generation both in patients with schizophrenia and spectrum disorders and their relatives.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
36Curr Psychiatry Rep 2005 Apr 7: 143-51
PMID15802092
TitleMeta-analysis in psychiatric genetics.
AbstractThe article reviews literature on methods for meta-analysis of genetic linkage and association studies, and summarizes and comments on specific meta-analysis findings for psychiatric disorders. The Genome Scan Meta-Analysis and Multiple Scan Probability methods assess the evidence for linkage across studies. Multiple Scan Probability analysis suggested linkage of two chromosomal regions (13q and 22q) to schizophrenia and bipolar disorder, whereas Genome Scan Meta-Analysis on a larger sample identified at least 10 schizophrenia linkage regions, but none for bipolar disorder. Meta-analyses of pooled ORs support association of schizophrenia to the Ser311Cys polymorphism in DRD2 and the T102C polymorphism in HTR2A, and of attention deficit hyperactivity disorder to the 48-bp repeat in DRD4. The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown. Meta-analyses support linkage of schizophrenia to regions where replicable associations to candidate genes have been identified through positional cloning methods. There are additional supported regions where susceptibility genes are likely to be identified. Linkage meta-analysis has had less clear success for bipolar disorder based on a smaller dataset. Meta-analysis can guide the prioritization of regions for study, but proof of association requires biological confirmation of hypotheses about gene actions. Elucidation of causal mechanisms will require more comprehensive study of sequence variation in candidate genes, better statistical and meta-analytic methods to take all variation into account, and biological strategies for testing etiologic hypotheses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
37Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 42-7
PMID16252386
Title[Dopamine receptor DRD4 gene polymorphism and its association with schizophrenia spectrum disorders and personality traits of patients].
AbstractA vast body of associative studies reported a role of highly polymorphic dopamine receptor DRD4 gene in regulation of emotional processes and development of mental disorders. The present study addresses allele, genotype and haplotype distribution of 3 polymorphic DRD4 markers (-809G/A, -616G/C N -521C/T) in Russian patients with schizophrenia spectrum disorders and their relation to the disease and personality traits. A sample included 151 patients with iCD-10 diagnosis of schizophrenia, schizoaffective psychosis and schizotypal personality disorders, 89 their first-degree non-psychotic relatives and 131 mentally healthy individuals. No differences in allele and genotype frequency was found between the patients and the controls. Transmission disiquilibrium test (TDT) did not reveal a preferential transmission of either allele from parents to proband. The 521C/T N -616G/C markers were linked to the disease when the EH program has been used in the analysis. Patients with the GG (-809G/A) and GG (-616G/C) genotypes had higher scores on the Hypomania scale (MMPI) comparing to the GA(-809G/A)+AA(-809G/A) and GC(-616G/C)+CC(-616G/C) genotypes but the association did not reach a level of significance (p = 0.06). The results confirmed the literature reports on the relation of the DRD4 gene to schizophrenia and personality traits related to social activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
38Neuropsychobiology 2005 -1 51: 3-9
PMID15627807
TitleInteraction between the tryptophan hydroxylase gene and the serotonin transporter gene in schizophrenia but not in bipolar or unipolar affective disorders.
AbstractIncreasing focus is being given to identify possible combinations of genes related to specific clinical phenotypes. In our sample of 814 patients comprising 114 with schizophrenia, 416 with bipolar affective disorder and 284 with unipolar affective disorder, we studied interactions between the tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR), and the dopamine receptor (DRD4) genes in relation to five major psychiatric symptomatology scores. There was significant interaction between the TPH and the 5-HTTLPR genes. With an increasing number of short (s) alleles of 5-HTTLPR, the scores for delusions, disorganization and negative symptoms were significantly decreasing among subjects having the TPH genotype AA but increasing among subjects having the TPH genotype AC, yielding the highest scores for the combinations AA x ll and AC x ss. Since high scores on just delusions, disorganization and negative symptoms but low scores on excitement and depression were found among subjects with schizophrenia, we conducted comparisons among the three diagnostic categories and controls as regards the combined TPH x 5-HTTLPR genotype distribution. schizophrenia subjects had a significantly different distribution of the genotype combination for TPH x 5-HTTLPR as compared to 241 controls or to unipolar or bipolar subjects, and had significantly higher frequencies of AA x ll and of AC x ss. Thus, an interaction between TPH and 5-HTTLPR genes constitutes susceptibility to schizophrenia, thereby yielding apparent relationships between the major psychiatric symptomatology scores and genotype combinations in samples that are obtained by pooling schizophrenia with other diagnostic categories.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
39J Neural Transm (Vienna) 2005 Nov 112: 1575-82
PMID15785860
TitleAn association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia.
AbstractDopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
40Zh Nevrol Psikhiatr Im S S Korsakova 2005 -1 105: 42-7
PMID16252386
Title[Dopamine receptor DRD4 gene polymorphism and its association with schizophrenia spectrum disorders and personality traits of patients].
AbstractA vast body of associative studies reported a role of highly polymorphic dopamine receptor DRD4 gene in regulation of emotional processes and development of mental disorders. The present study addresses allele, genotype and haplotype distribution of 3 polymorphic DRD4 markers (-809G/A, -616G/C N -521C/T) in Russian patients with schizophrenia spectrum disorders and their relation to the disease and personality traits. A sample included 151 patients with iCD-10 diagnosis of schizophrenia, schizoaffective psychosis and schizotypal personality disorders, 89 their first-degree non-psychotic relatives and 131 mentally healthy individuals. No differences in allele and genotype frequency was found between the patients and the controls. Transmission disiquilibrium test (TDT) did not reveal a preferential transmission of either allele from parents to proband. The 521C/T N -616G/C markers were linked to the disease when the EH program has been used in the analysis. Patients with the GG (-809G/A) and GG (-616G/C) genotypes had higher scores on the Hypomania scale (MMPI) comparing to the GA(-809G/A)+AA(-809G/A) and GC(-616G/C)+CC(-616G/C) genotypes but the association did not reach a level of significance (p = 0.06). The results confirmed the literature reports on the relation of the DRD4 gene to schizophrenia and personality traits related to social activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
41Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7
PMID17109713
TitleSchizotypy, attention deficit hyperactivity disorder, and dopamine genes.
AbstractPrevious research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
42Zh Nevrol Psikhiatr Im S S Korsakova 2006 -1 106: 57-63
PMID16921721
Title[Dopamine system genes interaction and neurocognitive traits in patients with schizophrenia, their relatives and healthy controls from general population].
AbstractTo elucidate main effects of dopamine receptor D4 (DRD4) and cathecol-O-methyltransferase (COMT) genes as well as their interaction effect on neurocognitive traits, DRD4 gene polymorphisms (-809G/A, -521C/T) and the COMT gene Val158Met polymorphism, along with characteristics of verbal memory, executive functions and peculiarities of associative processes, have been studied in 150 patients with schizophrenia, 83 their relatives and 118 mentally healthy subjects without positive family history of psychosis. A main effect of -521C/T polymorphism and DRD4 (-521C/T).Vall58Met polymorphisms interaction were found for verbal fluency, carriers of the Val/Val+CC and the Met/Met+TT genotypes performing better on this task as compared to other genotypes. An interaction DRD4 (-521C/T).Val158Met effect on originality of speech associations was observed in the combined group of unaffected individuals (relatives and controls), with lower scores of the trait in those with the Met/Met+CC genotype. The COMT-DRD4 (-809G/A) interaction effect on working memory was demonstrated for patients and unaffected individuals, homozygotes for the Val and the G alleles having the best results and homozygotes for the Met and the A alleles--the worst ones. The data obtained suggest the relationship of DRD4 and COMT genes with different characteristics of executive functions but not with verbal memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
43Pharmacogenet. Genomics 2006 Feb 16: 111-7
PMID16424823
TitleGenetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms.
AbstractTardive dyskinesia (TD) is an antipsychotic induced side effect observed in 20-30% of schizophrenia subjects on long-term typical antipsychotic treatment. We tested the possible association of 24 polymorphisms from six dopaminergic genes: namely, dopamine receptors D1, D2, D3, D4; the dopamine transporter (DAT); and the catalyzing enzyme catechol-O-methyltransferase (COMT), with TD.
Multiple SNP/VNTR markers from candidate genes were analyzed using suitable approaches and allelic, genotypic and haplotypic associations were tested.
120 bp duplication marker, 1.2 kb upstream from initiation codon of DRD4 gene showed a significant genotypic association [chi2 = 9.29, P = 0.009; OR (95% CI) = 0.52 (0.31-0.86) for genotype 120 dup/120 dup]. In the COMT gene, a significant allelic [chi2 = 13.87, P = 0.0002] as well as genotypic association [chi2 = 16.08, P = 0.0003; OR (95% CI) = 0.24 (0.11-0.55) for genotype GG] was observed with the 408 C>G (exon 4) single nucleotide polymorphism and a significant genotypic association [chi2 = 6.32, P = 0.04; OR (95% CI) = 0.50 (0.33-0.92) for genotype GG] was observed with 472 G > A (exon 4, Val 158 Met) SNP. 120 bp dup-T-repeat 3 in DRD4 and G-C-A-insC in COMT genes were observed to be TD associated haplotypes.
Our study presents a detailed analysis of the possible role of dopaminergic genes in the genesis of TD. DRD4 and COMT genes were observed to be the most important candidates in North Indian schizophrenia subjects. These suggestive associations need to be investigated in replicate studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
44Psychiatr. Genet. 2006 Aug 16: 139-43
PMID16829780
TitleDopamine D4 receptor gene and the -521C>T polymorphism of the upstream region of the dopamine D4 receptor gene in schizophrenia.
AbstractThe dopamine D4 receptor (DRD4) is a candidate gene for increasing genetic susceptibility to schizophrenia. A recent study found that a -521C>T promoter base pair change affects transcriptional regulation of the DRD4 gene. The present study was designed to investigate the role of both the -521C>T single nucleotide polymorphism and the DRD4 variable number tandem repeat (VNTR) polymorphism.
A case-control study of 630 Chinese schizophrenic patients and 428 Chinese controls was conducted to test for allelic association with schizophrenia.
The number of DRD4 VNTR fragments was associated with schizophrenia. Long DRD4 VNTR fragments as opposed to short fragments were commoner in schizophrenia. No evidence was found for allelic association between the -521C>T DRD4 polymorphism and schizophrenia.
This study provides preliminary and unconfirmed evidence for the involvement of the DRD4 repeat VNTR in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
45Neurotox Res 2006 Dec 10: 167-79
PMID17197367
TitleDopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.
AbstractThe basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
46Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7
PMID17109713
TitleSchizotypy, attention deficit hyperactivity disorder, and dopamine genes.
AbstractPrevious research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
47Psychiatry Clin. Neurosci. 2006 Dec 60: 764-7
PMID17109713
TitleSchizotypy, attention deficit hyperactivity disorder, and dopamine genes.
AbstractPrevious research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
48Neurotox Res 2006 Dec 10: 167-79
PMID17197367
TitleDopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.
AbstractThe basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
49Psychiatr. Genet. 2006 Aug 16: 139-43
PMID16829780
TitleDopamine D4 receptor gene and the -521C>T polymorphism of the upstream region of the dopamine D4 receptor gene in schizophrenia.
AbstractThe dopamine D4 receptor (DRD4) is a candidate gene for increasing genetic susceptibility to schizophrenia. A recent study found that a -521C>T promoter base pair change affects transcriptional regulation of the DRD4 gene. The present study was designed to investigate the role of both the -521C>T single nucleotide polymorphism and the DRD4 variable number tandem repeat (VNTR) polymorphism.
A case-control study of 630 Chinese schizophrenic patients and 428 Chinese controls was conducted to test for allelic association with schizophrenia.
The number of DRD4 VNTR fragments was associated with schizophrenia. Long DRD4 VNTR fragments as opposed to short fragments were commoner in schizophrenia. No evidence was found for allelic association between the -521C>T DRD4 polymorphism and schizophrenia.
This study provides preliminary and unconfirmed evidence for the involvement of the DRD4 repeat VNTR in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
50J. Neurosci. 2007 Dec 27: 14190-8
PMID18094258
TitleThe impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring.
AbstractDynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMT Val allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
51Neurosci. Behav. Physiol. 2007 Sep 37: 643-50
PMID17763983
TitleInteraction of dopamine system genes and cognitive functions in patients with schizophrenia and their relatives and in healthy subjects from the general population.
AbstractLinkage between the DRD4 and COMT genes and cognitive measures characterizing verbal memory, executive functions, and associative processes was studied in 150 patients with schizophrenia, 83 of their relatives, and 118 mentally healthy subjects without any family history of psychoses, with the aim of detecting the main effects of the polymorphic markers -809G/A and -521C/T (DRD4) and Val158Met (COMT) when present individually and together. The group of patients showed a main effect for polymorphism -521C/T on verbal fluency and an effect of the interaction of this polymorphism and the COMT gene on this cognitive trait. The highest level of verbal fluency was seen among carriers of the Val/Val+CC and Met/Met+TT genotypes. In the combined group of unaffected individuals, the interaction of the COMT and DRD4 -521C/TT genotypes had an effect on the standardness of speech associations due to a decrease in the standardness of associations in carriers of the Met/Met+CC genotype. Finally, both patients and unaffected individuals showed an effect for the interaction between the COMT and DRD4 -809G/A genotypes on working memory. Patients and healthy subjects showed similar features: the highest values were seen in subjects homozygous for the Val and G alleles, while the lowest values were seen in homozygotes for the Met and A alleles. These data provide evidence for a relationship between the DRD4 and COMT genes and different aspects of executive functions and the absence of such a relationship in relation to verbal memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
52Cereb. Cortex 2007 May 17: 1007-19
PMID16751296
TitleDRD4 and DAT1 polymorphisms modulate human gamma band responses.
AbstractGamma oscillations (30-80 Hz) have been demonstrated to be important for perceptual and cognitive processes. Animal and in vitro studies have revealed possible underlying generation mechanisms of the gamma rhythm. However, little is known about the neurochemical modulation of these oscillations during human cognition. schizophrenia and Attention Deficit Hyperactivity Disorder, which lead to failure of attentional modulation and working memory, introduce significant changes in gamma responses and have significant associations with genetic polymorphisms of dopamine receptor D4 (DRD4), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT). Therefore, the presence of direct relations between these polymorphisms and gamma oscillations was investigated in human subjects using an auditory target detection paradigm. The 7-repeat isoform of the DRD4 polymorphism that produces a subsensitive variant of the D4 receptor enhanced the auditory evoked and induced gamma responses to both standard and target stimuli. The 10/10 genotype of the DAT1 polymorphism, which reduces DAT expression and hence yields an increase in extracellular dopamine, specifically enhanced evoked gamma responses to target stimuli. The COMT polymorphism did not significantly change gamma responses. It seems plausible to assume that the modulation pattern of the evoked gamma response by DRD4 polymorphism relates to reduced inhibition via the D4 receptor, whereas the DAT1 effect is related to the target detection mechanism probably mediated by the D1 receptor.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
53Psychiatry Res 2007 Dec 153: 209-15
PMID17822780
TitleAssociation analysis of exon III and exon I polymorphisms of the dopamine D4 receptor locus in Mexican psychotic patients.
AbstractIn this study, we investigated whether polymorphisms of the dopamine D4 receptor (DRD4) gene were associated with psychotic symptomatology rather than with a unique diagnosis such as schizophrenia. A number of association studies between the DRD4 gene 48 bp-VNTR polymorphism at exon 3 and psychotic disorders have been reported, but the results have been controversial. Both 48 bp-VNTR and the 12 bp-VNTR (at exon 1) polymorphisms of this gene were analyzed in a group of 149 unrelated Mexican subjects with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depression and bipolar disorder, both with psychotic symptoms, brief psychotic disorder, delusional disorder and non-specific psychotic disorder, and in 169 individuals free of psychiatric illnesses. There were no differences in allele or genotype frequencies between groups for the 12 bp-VNTR polymorphisms. However, a significant excess of "rare" alleles (3-, 5-, 6- and 8-48 bp repeats alleles) was found in the group of psychotics. Moreover, haplotypes 3-A1, 5-A1, 6-A1 and 8-A1 were significantly more frequently associated with cases. This positive association supports a role of this molecule as a genetic risk factor in psychotic disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
54Neuropsychobiology 2007 -1 55: 171-5
PMID17657171
TitleAssociation study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior.
AbstractGenes involved in dopamine neurotransmission are interesting candidates to be analyzed in schizophrenia and aggressive behavior. Therefore, we analyzed the functional polymorphisms of the dopamine receptor D4 (DRD4) and monoamine oxidase A (MAO-A) genes in a sample of 71 schizophrenic patients assessed with the Overt Aggression Scale to measure aggressive behavior. CLUMP analysis of the DRD4 48-bp repeat-exon III polymorphism in schizophrenic patients showed significant differences between the aggressive behavior and the nonaggressive groups (T1 = 18.77, d.f. = 6, p = 0.0046; T3 = 6.54, p = 0.0195). However, analysis of the promoter polymorphism of the MAO-A gene revealed no significant association between aggressive and nonaggressive patients. Finally, analysis of Overt Aggression Scale dimensions exhibited significant differences for the DRD4 and MAO-A genes. Our preliminary findings suggest that the DRD4 and MAO-A genes may be involved in aggressive schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
55Neuropsychobiology 2007 -1 55: 47-51
PMID17556853
TitleNo association between dopamine D4 receptor gene -521 C/T polymorphism and tardive dyskinesia in schizophrenia.
AbstractTardive dyskinesia (TD) is a long-term adverse effect of antipsychotics. We evaluated whether a candidate functional polymorphism of the dopamine D4 receptor (DRD4) gene is associated with drug-induced TD in 209 Korean schizophrenic patients with TD (n = 83) and without TD (n = 126) who were matched for antipsychotic drug exposure and other relevant variables. There was no significant association of the genotype and allele frequencies determined by the -521 C/T SNP of DRD4 between TD and non-TD patients. In addition, there was no significant difference in terms of total Abnormal Involuntary Movement Scale scores among the 3 genotype groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that the DRD4 -521 C/T SNP does not contribute significantly to the risk for TD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
56J. Hum. Genet. 2007 -1 52: 86-91
PMID17089069
TitleAssociation and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics.
AbstractRecent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (-1106T>C, -906T>C, -809G>A, -616G>C, -521T>C, -376C>T, -291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) -809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, -809G>A, -616G>C, -291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
57J Psychiatr Res 2007 Nov 41: 763-75
PMID16887146
TitleGenetic structure of the dopamine receptor D4 gene (DRD4) and lack of association with schizophrenia in Japanese patients.
AbstractIn order to investigate the contribution of genetic variation in the human dopamine receptor D4 gene (DRD4) to the risk of developing schizophrenia, we carried out a genetic analysis of 27 polymorphisms in 216 schizophrenic patients and 243 healthy controls from the Kyushu region of Japan. Twenty-two single nucleotide polymorphisms (SNPs) and five insertion/deletion polymorphisms were analyzed in this study, including four novel SNPs and a novel mononucleotide repeat. Linkage disequilibrium (LD) and haplotype analyses reveal weak LD across the DRD4 gene. In univariate analysis female individuals with allele -521C had a higher risk for schizophrenia. However, this finding was not significant after correction for multiple hypothesis testing. No other polymorphisms or haplotypes differed between schizophrenic patients and controls. Likewise, multivariate analyses did not reveal any statistically significant associations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
58Neuropsychobiology 2007 -1 55: 171-5
PMID17657171
TitleAssociation study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior.
AbstractGenes involved in dopamine neurotransmission are interesting candidates to be analyzed in schizophrenia and aggressive behavior. Therefore, we analyzed the functional polymorphisms of the dopamine receptor D4 (DRD4) and monoamine oxidase A (MAO-A) genes in a sample of 71 schizophrenic patients assessed with the Overt Aggression Scale to measure aggressive behavior. CLUMP analysis of the DRD4 48-bp repeat-exon III polymorphism in schizophrenic patients showed significant differences between the aggressive behavior and the nonaggressive groups (T1 = 18.77, d.f. = 6, p = 0.0046; T3 = 6.54, p = 0.0195). However, analysis of the promoter polymorphism of the MAO-A gene revealed no significant association between aggressive and nonaggressive patients. Finally, analysis of Overt Aggression Scale dimensions exhibited significant differences for the DRD4 and MAO-A genes. Our preliminary findings suggest that the DRD4 and MAO-A genes may be involved in aggressive schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
59Neuropsychobiology 2007 -1 55: 47-51
PMID17556853
TitleNo association between dopamine D4 receptor gene -521 C/T polymorphism and tardive dyskinesia in schizophrenia.
AbstractTardive dyskinesia (TD) is a long-term adverse effect of antipsychotics. We evaluated whether a candidate functional polymorphism of the dopamine D4 receptor (DRD4) gene is associated with drug-induced TD in 209 Korean schizophrenic patients with TD (n = 83) and without TD (n = 126) who were matched for antipsychotic drug exposure and other relevant variables. There was no significant association of the genotype and allele frequencies determined by the -521 C/T SNP of DRD4 between TD and non-TD patients. In addition, there was no significant difference in terms of total Abnormal Involuntary Movement Scale scores among the 3 genotype groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that the DRD4 -521 C/T SNP does not contribute significantly to the risk for TD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
60J. Hum. Genet. 2007 -1 52: 86-91
PMID17089069
TitleAssociation and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics.
AbstractRecent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (-1106T>C, -906T>C, -809G>A, -616G>C, -521T>C, -376C>T, -291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) -809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, -809G>A, -616G>C, -291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
61J. Hum. Genet. 2007 -1 52: 86-91
PMID17089069
TitleAssociation and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics.
AbstractRecent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (-1106T>C, -906T>C, -809G>A, -616G>C, -521T>C, -376C>T, -291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) -809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, -809G>A, -616G>C, -291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
62J Psychiatr Res 2007 Nov 41: 763-75
PMID16887146
TitleGenetic structure of the dopamine receptor D4 gene (DRD4) and lack of association with schizophrenia in Japanese patients.
AbstractIn order to investigate the contribution of genetic variation in the human dopamine receptor D4 gene (DRD4) to the risk of developing schizophrenia, we carried out a genetic analysis of 27 polymorphisms in 216 schizophrenic patients and 243 healthy controls from the Kyushu region of Japan. Twenty-two single nucleotide polymorphisms (SNPs) and five insertion/deletion polymorphisms were analyzed in this study, including four novel SNPs and a novel mononucleotide repeat. Linkage disequilibrium (LD) and haplotype analyses reveal weak LD across the DRD4 gene. In univariate analysis female individuals with allele -521C had a higher risk for schizophrenia. However, this finding was not significant after correction for multiple hypothesis testing. No other polymorphisms or haplotypes differed between schizophrenic patients and controls. Likewise, multivariate analyses did not reveal any statistically significant associations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
63Ann. N. Y. Acad. Sci. 2008 -1 1129: 200-12
PMID18591481
TitleMolecular genetics of attention.
AbstractThe sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-epsilon4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
64Psychiatry Res 2008 Dec 161: 275-83
PMID19000940
TitleCorrelates of response to Olanzapine in a North Indian Schizophrenia sample.
AbstractOlanzapine is widely used for the treatment of schizophrenia and is considered a first line medication in India. Along with other factors, the variation in response and side effects to this agent may be accounted for by genetic differences among patients. Olanzapine was administered for 6 weeks to Indian subjects with schizophrenia or schizoaffective disorder (DSM-IV, n=130), as part of an open label study. Intent-to-treat analysis was performed, and 10 polymorphic markers from seven genes (dopamine D1, D2, D3 and D4 receptors, serotonin 2A receptor and the drug-metabolizing enzymes (CYP1A2 and CYP2D6)), together with demographic and clinical variables, were analyzed as potential predictors of response. Olanzapine was efficacious, but significant weight gain was noted. Baseline weight and a 120 bp deletion polymorphism at the dopamine receptor D4 (DRD4) gene were associated with changes in symptom scores. Predictable covariates of treatment response were also noted. These results merit replicate studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
65Nat. Genet. 2008 Jul 40: 827-34
PMID18583979
TitleSystematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.
AbstractIn an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
66Schizophr. Res. 2008 Sep 104: 96-107
PMID18715757
TitleGenetic associations with schizophrenia: meta-analyses of 12 candidate genes.
AbstractGenetic association studies on schizophrenia (SZ) have been repeatedly performed over the last two decades, resulting in a consensus that results are generally inconsistent. This consensus has begun to change as a result of meta-analyses (e.g., [Glatt, S.J. and Jonsson, E.G., 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 149-154.]). The schizophreniaGene database (http://www.schizophreniaforum.org/res/sczgene/default.asp) has been a leader in meta-analyses of SZ association data, by dynamically and comprehensively cataloging all public genetic association studies, and preparing meta-analyses of case-control data. There are 19 "top" candidate genes from these analyses (access on December 20, 2007), showing the highest effect sizes and nominally significant associations of at least one variant in the meta-analyses of all ethnic samples or of samples of Caucasian ancestry. We selected 40 polymorphisms in 12 selected "top" genes for additional meta-analyses, which had at least one familial association data. We found gene-wide (correction for the number of meta-analyses for each gene) significant allelic association evidence for seven genes in the combined samples. The odds ratios (ORs) of the associated minor risk alleles range from 1.072 to 1.121, for DRD4, MTHFR, PPP3CC and TP53. For protective allele associations, the ORs are between 0.842 and 0.886, for DAO, IL1B, and SLC6A4. In population-based sub-analyses, we found significant results in four genes in Asians (ORs between 1.084 and 1.309 for DRD4, GABRB2, PPP3CC, and TP53), and one gene in European (OR of 0.888 for SLC6A4). The association of rs1816072 of GABRB2 with SZ in Asians was significant (adjusted P=0.048 after correction for 80 tests). No significant heterogeneity between case-control and family-based study designs was detected in 35 out of 40 polymorphisms. Our results further support eight potential SZ candidate genes and suggest that family data can reasonably be included in the meta-analysis of genetic associations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
67Ann Biomed Eng 2008 Jun 36: 877-88
PMID18330705
TitlePhysiogenomic analysis of localized FMRI brain activity in schizophrenia.
AbstractThe search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
68Neuropsychobiology 2008 -1 57: 49-54
PMID18451638
TitleAssociation study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia.
AbstractThe cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia.
We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions.
We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05).
These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
69Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1491-5
PMID18579277
TitleAssociation between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients.
AbstractHyperprolactinemia is an inevitable consequence of treatment with antipsychotic agents to some extent because prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that polymorphisms of the dopamine receptors are associated with therapeutic response to antipsychotics. Thus, we studied the effects of major polymorphisms of dopamine-related genes on plasma concentration of prolactin. Subjects were 174 schizophrenic patients (68 males, 106 females) receiving 3 mg twice daily of risperidone for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. Five dopamine-related polymorphisms (Taq1A, -141C ins/del for DRD2, Ser9Gly for DRD3, 48 bp VNTR for DRD4, Val158Met for COMT) were identified. The mean (+/-SD) plasma concentration of prolactin in females was significantly higher than males (54.3+/-27.2 ng/ml versus 126.8+/-70.2 ng/ml, p<0.001). No dopamine-related polymorphisms differed the plasma concentration of prolactin in males or females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized partial correlation coefficients (beta)=0.551, p<0.001) and negatively with age (standardized beta=-0.202, p<0.01). No correlations were found between prolactin concentration and dopamine-related polymorphisms. These findings suggest that plasma prolactin concentrations in females are much higher than in males but the dopamine-related variants are not predominantly associated with plasma concentration of prolactin.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
70Neuropsychobiology 2008 -1 57: 49-54
PMID18451638
TitleAssociation study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia.
AbstractThe cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia.
We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions.
We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05).
These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
71Pharmacogenomics J. 2009 Jun 9: 168-74
PMID19238168
TitleAssociation study of tardive dyskinesia and five DRD4 polymorphisms in schizophrenia patients.
AbstractTardive dyskinesia (TD) is a side effect of chronic antipsychotic medication exposure. Abnormalities in dopaminergic activity in the nigro-striatal system have been most often suggested to be involved because the agents that cause TD share in common potent antagonism of dopamine D(2) receptors (DRD2). Thus, a number of studies have focused on the association of dopamine system gene polymorphisms and TD, with the most consistent findings being an association between TD and the Ser9Gly polymorphism of the DRD3 gene and the TaqIA site 3' of the DRD2 gene. The DRD4 gene codes for the third member of the D(2)-like dopamine receptor family, and the variable number tandem-repeat polymorphism in exon 3 of DRD4 has been associated with TD. However, other polymorphisms have not been thoroughly examined. In this study, we investigated five polymorphisms spanning the DRD4 gene and their association with TD in our European Caucasian sample (N=171). Although the exon 3 variable number tandem repeat was not associated with TD, haplotypes consisting of four tag polymorphisms were associated with TD in males. This study suggests that DRD4 may be involved in TD in the Caucasian population, although further replication studies are needed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
72Croat. Med. J. 2009 Aug 50: 361-9
PMID19673036
TitleAssociation of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population.
AbstractTo perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population.
A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit chi(2) test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis.
Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tagSNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P<0.005). A trend test also confirmed the genotypic association (P<0.001) of these 4 tagSNPs. Additionally, moderate association (P<0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT.
Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
73Psychiatry Investig 2009 Sep 6: 222-5
PMID20046399
TitleGenetic polymorphisms in dopamine- and serotonin-related genes and treatment responses to risperidone and perospirone.
AbstractWe investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
74BMC Med. Genet. 2009 -1 10: 147
PMID20040103
TitleAssociation of DRD4 uVNTR and TP53 codon 72 polymorphisms with schizophrenia: a case-control study.
AbstractThe tumour supressor gene TP53 is thought to be involved in neural apoptosis. The polymorphism at codon 72 in TP53 and the long form variants of the upstream variable number of tandem repeats (uVNTR) polymorphism in the dopamine D4 receptor (DRD4) gene are reported to confer susceptibility to schizophrenia.
We recruited 934 patients with schizophrenia and 433 healthy individuals, and genotyped the locus of the TP53 codon 72 and DRD4 uVNTR polymorphisms by combining the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) with direct sequencing.
No significant differences were found in the frequency of the genotype of the TP53 codon72 polymorphism between patients with schizophrenia and their controls. However, the long form alleles (> or = 5 repeats) of the DRD4 uVNTR polymorphism were more frequent in patients with schizophrenia than in controls (p = 0.001). Hence, this class of alleles might be a risk factor for enhanced vulnerability to schizophrenia (odds ratio = 3.189, 95% confidence interval = 1.535-6.622). In the logistic regression analysis, the long form variants of the DRD4 polymorphism did predict schizophrenia after the contributions of the age and gender of the subjects were included (p = 0.036, OR = 2.319), but the CC and GG genotypes of the codon 72 polymorphism of TP53 did not.
The long form variants of the uVNTR polymorphism in DRD4 were associated with schizophrenia, in a manner that was independent of the TP53 codon 72 polymorphism. In addition, given that the genetic effect of the TP53 codon 72 polymorphism on the risk of developing schizophrenia was very small, this polymorphism is unlikely to be associated with schizophrenia. The roles that other single nucleotide polymorphisms (SNPs) in the TP53 gene or in other apoptosis-related genes play in the synaptic dysfunction involved in the pathogenesis of schizophrenia should be investigated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
75Prim Care Companion J Clin Psychiatry 2009 -1 11: 16-20
PMID19333405
TitleProlactin levels in olanzapine treatment correlate with positive symptoms of schizophrenia: results from an open-label, flexible-dose study.
AbstractThis study was designed to investigate the relationship between the treatment effect of olanzapine and the serum prolactin level in schizophrenia and to investigate the factors that may act as predictors of response for olanzapine treatment.
Sixty patients who met the DSM-IV criteria for schizophrenia were included in the study. None of the patients were drug-naive, and they were given olanzapine in a flexible dose of 10-30 mg/day for 3 months after a 7-day drug washout period. Serum prolactin levels were measured at baseline (after drug washout) and at months 1, 2, and 3 during olanzapine treatment. A psychiatrist performed monthly ratings of symptoms using the Positive and Negative Syndrome Scale Manual (PANSS Manual). The Generalized Estimating Equations-I was used for data correlation analysis. Data were gathered from July 2005 to July 2006.
In general, the serum prolactin level was decreased in schizophrenia patients with olanzapine treatment, although the difference is not statistically significant (p = .974, p = .246, and p = .363 for the first, second, and third months, respectively). There was a close relationship between the improvement in positive symptoms and the change in serum prolactin levels before and after olanzapine treatment (p = .002). Moreover, the serum prolactin level also had a positive association with female gender (p = .008). The present study demonstrated no significant correlation between serum prolactin level, MAOA polymorphism, and DRD4 genotype.
This finding suggests that the serum prolactin level may be a useful biological marker to predict the effectiveness of antipsychotics in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
76Eur. J. Hum. Genet. 2009 Jun 17: 793-801
PMID19092778
TitleVariable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia.
AbstractAssociations have been reported between the variable number of tandem repeat (VNTR) polymorphisms in the exon 3 of dopamine D4 receptor gene gene and multiple psychiatric illnesses/traits. We examined the distribution of VNTR alleles of different length in a Japanese cohort and found that, as reported earlier, the size of allele '7R' was much rarer (0.5%) in Japanese than in Caucasian populations (approximately 20%). This presents a challenge to an earlier proposed hypothesis that positive selection favoring the allele 7R has contributed to its high frequency. To further address the issue of selection, we carried out sequencing of the VNTR region not only from human but also from chimpanzee samples, and made inference on the ancestral repeat motif and haplotype by use of a phylogenetic analysis program. The most common 4R variant was considered to be the ancestral haplotype as earlier proposed. However, in a gene tree of VNTR constructed on the basis of this inferred ancestral haplotype, the allele 7R had five descendent haplotypes in relatively long lineage, where genetic drift can have major influence. We also tested this length polymorphism for association with schizophrenia, studying two Japanese sample sets (one with 570 cases and 570 controls, and the other with 124 pedigrees). No evidence of association between the allele 7R and schizophrenia was found in any of the two data sets. Collectively, this study suggests that the VNTR variation does not have an effect large enough to cause either selection or a detectable association with schizophrenia in a study of samples of moderate size.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
77Neuropsychopharmacology 2009 Jan 34: 436-45
PMID18536704
TitleDecreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum.
AbstractTo better understand the effect of the dopamine D4 receptor (DRD4) on glutamate (Glu) neurotransmission in the brain, we utilized transgenic mice with partial or complete removal of functional DRD4 plasma membrane expression (DRD4+/- and DRD4-/-, respectively). We measured resting extracellular Glu levels, Glu clearance kinetics, and KCl-evoked release of Glu in the striatum and nucleus accumbens core of these mice using in vivo amperometry coupled to a novel microelectrode array configured for sub-second detection of Glu. Recordings from DRD4-/- and DRD4+/- mice were compared with their wild-type littermates (DRD4+/+). Resting extracellular levels of Glu were increased in the striatum of DRD4-/- mice (p<0.01). Glu clearance kinetics were significantly decreased in the dorsal striatum of DRD4-/- mice (p<0.05). KCl-evoked overflow of Glu was reliably measured but unchanged in the striatum of the three groups. By contrast, no changes in resting Glu, Glu uptake kinetics, or KCl-evoked release of Glu were observed in the nucleus accumbens core among the three genotypes. These data indicate that the DRD4 receptor is involved in modulation of Glu neurotransmission, primarily in the striatum. A better understanding of Glu control by the DRD4 may improve our understanding of the physiological role of the DRD4 in disorders such as attention-deficit/hyperactivity disorder and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
78Psychiatry Investig 2009 Sep 6: 222-5
PMID20046399
TitleGenetic polymorphisms in dopamine- and serotonin-related genes and treatment responses to risperidone and perospirone.
AbstractWe investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
79Coll Antropol 2010 Dec 34: 1427-32
PMID21874733
TitleComparative study on gene tags of the neurotransmission system in schizophrenic and suicidal subjects.
Abstractschizophrenia and suicidal behaviour are sever and complex mental disorders, largely determined by factors of inheritance. Both disorders present pathological changes in the catecholamine neurotransmitter system. The study was conducted on three groups; a group of subjects suffering from schizophrenia, a second compounded by individuals who attempted suicide and a third group of phenotypically healthy examinees. The blood samples of schizophrenic patients as of those who attempted suicide were obtained at the Psychiatric Hospital "Sveti Ivan" in Zagreb in the year 2004. Tests were conducted on the statistic relation between a total of 18 SNPs within three candidate-genes of the dopamine and adrenergic system (DRD4, SLC6A3 and ADRA2B) and the manifestation of schzophrenia and suicidal behaviour. Cases were genotyped by use of SNPlex system. Statistically significant differences were determined in the allelic frequency between the mentioned groups. Findings show a significant connection between 4 SNPs (ADRA2B rs749457, SLC6A3 rs464094, DRD4 rs11246226 and rs4331145) and schizophrenia, and 2 SNPs with suicidal attempt (ADRA2B rs1018351 i SLC6A3 rs403636). In addition, this is the first study that highlights the potential role/effect of polymorphisms in ADRA2B on the manifestation of schizophrenia, as on suicidal behaviour.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
80Curr. Med. Chem. 2010 -1 17: 1300-16
PMID20166940
TitlePrimate-accelerated evolutionary genes: novel routes to drug discovery in psychiatric disorders.
AbstractNovel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
81Psychiatr. Genet. 2010 Oct 20: 191-8
PMID20421849
TitleHabituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B).
AbstractTo identify the reliable connectivity between causal genes or variants with an abnormality expressed in a certain endophenotype has been viewed as a crucial step in unraveling the etiology of schizophrenia because of the considerable heterogeneity in this disorder.
According to this practical and scientific demand, we aimed to investigate the relationship between seven top-ranked variants in the SZgene database [120-bpTR in DRD4, rs1801028 and rs6277 in DRD2, rs1019385 (T200G) in GRIN2B, rs1800532 in TPH1, rs1801133 (C677T) in MTHFR, rs2619528 (P1765) in DTNBP1] and prepulse inhibition (PPI) and habituation after acoustic stimulus (HAB).
Both PPI and HAB were decreased significantly in patients with schizophrenia. In addition, we observed a significant effect of GRIN2B (human NMDA receptor 2B subunit gene, NR2B) genotype on HAB (P<0.05, not corrected).
Although these findings need to be replicated in other samples, an underlying mechanism of impaired biological reaction may be influenced by NMDA hypofunctioning in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
82Brain Res. 2010 Nov 1359: 227-32
PMID20801104
TitleAssociation study of polymorphisms in the promoter region of DRD4 with schizophrenia, depression, and heroin addiction.
AbstractThis study investigated the possible association between three functional polymorphisms in the promoter region of the dopamine D4 receptor (DRD4) gene and schizophrenia, depression, and heroin addiction. Genomic DNA was isolated from the venous blood leukocytes of 322 unrelated patients with schizophrenia, 156 patients with depression, 300 patients with heroin addiction, and 300 healthy unrelated individuals. Polymorphisms in the promoter region of DRD4 (-120 bp duplication, -616C/G, and -521C/T) were genotyped using allele-specific polymerase chain reaction analysis. Genotype and allele were analyzed using SPSS 11.5 software. Results of this analysis indicated that there is a strong finding of -120 bp duplication allele frequencies with schizophrenia (p=0.008) and weak finding with -1240 L/S and for paranoid schizophrenia (p=0.022). Interestingly, there is a stronger finding with -521 C/T allele frequencies with heroin dependence (p=0.0002). These observations strongly suggest that the -120-bp duplication polymorphism of DRD4 is associated with schizophrenia and that the -521 C/T polymorphism is associated with heroin addiction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
83Coll Antropol 2010 Dec 34: 1427-32
PMID21874733
TitleComparative study on gene tags of the neurotransmission system in schizophrenic and suicidal subjects.
Abstractschizophrenia and suicidal behaviour are sever and complex mental disorders, largely determined by factors of inheritance. Both disorders present pathological changes in the catecholamine neurotransmitter system. The study was conducted on three groups; a group of subjects suffering from schizophrenia, a second compounded by individuals who attempted suicide and a third group of phenotypically healthy examinees. The blood samples of schizophrenic patients as of those who attempted suicide were obtained at the Psychiatric Hospital "Sveti Ivan" in Zagreb in the year 2004. Tests were conducted on the statistic relation between a total of 18 SNPs within three candidate-genes of the dopamine and adrenergic system (DRD4, SLC6A3 and ADRA2B) and the manifestation of schzophrenia and suicidal behaviour. Cases were genotyped by use of SNPlex system. Statistically significant differences were determined in the allelic frequency between the mentioned groups. Findings show a significant connection between 4 SNPs (ADRA2B rs749457, SLC6A3 rs464094, DRD4 rs11246226 and rs4331145) and schizophrenia, and 2 SNPs with suicidal attempt (ADRA2B rs1018351 i SLC6A3 rs403636). In addition, this is the first study that highlights the potential role/effect of polymorphisms in ADRA2B on the manifestation of schizophrenia, as on suicidal behaviour.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
84Acta Neurobiol Exp (Wars) 2010 -1 70: 86-94
PMID20407490
TitleInfluence of dopaminergic and serotoninergic genes on working memory in healthy subjects.
AbstractWorking memory is an ability to keep information in short-term memory and manipulate them 'on line'. Working memory is also involved in complex frontal executive functions. The role of dopaminergic system in modulating working memory processes in prefrontal cortex is well established. Also the role of serotoninergic receptors is postulated. The purpose of this study was to assess the association between the polymorphisms of dopaminergic (DRD1, DRD3, DRD4, COMT) and serotoninergic (SERT--serotonin transporter, 5HT2A, 5HT2C) genes' polymorphisms and performance on WCST in 200 volunteers from the Polish population. We found the association between DRD1, DRD4, COMT and SERT genes polymorphisms and the performance on WCST. The results obtained in the study indicate that dopaminergic and serotoninergic genes may play a role in modulating the executive function and working memory processes in healthy subjects. The pattern of this influence may be different in males and females. Moreover, the relationship between the efficacy of prefrontal cognitive function and genes polymorphisms may differ between healthy subjects and schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
85Behav. Genet. 2010 May 40: 415-23
PMID20033274
TitleCatechol-o-methyltransferase genotype and childhood trauma may interact to impact schizotypal personality traits.
AbstractWe attempt to identify gene by childhood abuse interactions which predispose to the development of schizotypal traits in a familial bipolar disorder (BD) sample. Self-report measures of schizotypal personality traits (schizotypal Personality Scale) and childhood maltreatment (Childhood Trauma Questionnaire) were administered to 222 participants from 44 families with BD. Variants of catechol-o-methyltransferase (COMT) and four other dopamine pathway-related genes: DRD4, DRD2,MAOA, and SLC6A3, were typed. BD type I (BD I) subjects scored significantly higher than their unaffected relatives on the schizotypal Personality Scale. The val allele of the Val158 Met polymorphism of the COMT gene was associated with increased schizotypal personality trait scores in individuals exposed to higher levels of self-reported childhood trauma (p < 0.05). There was no direct effect of the val158met polymorphism on schizotypal personality traits. Further, no passive correlation between COMT genotype and childhood trauma was found. We raise the possibility that genetically-driven variation in COMT may interact with childhood trauma to contribute to the risk of developing schizotypal personality traits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
86Mol. Biol. Rep. 2011 Apr 38: 2569-72
PMID21110120
TitleIs the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia?
Abstractschizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
87Psychiatry Res 2011 Jul 188: 294-6
PMID21216474
TitleThe interleukin 10 promoter haplotype ACA and the long-form variant of the DRD4 uVNTR polymorphism are associated with vulnerability to schizophrenia.
AbstractA total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin-10 (IL-10) promoter and DRD4 uVNTR polymorphisms. DRD4 long-form variants (namely, those with ?5 repeats), homozygosity for the 4-repeat allele, and the IL-10 haplotype ACA were associated with schizophrenia, respectively. No obvious interactions among the potential polymorphisms were found, which suggests that IL-10 and DRD4 confer vulnerability to schizophrenia independently.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
88Neuropsychopharmacology 2011 Jun 36: 1385-96
PMID21412225
TitleDopamine receptor mediation of the exploratory/hyperactivity effects of modafinil.
AbstractModafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, drd2, drd3, and DRD4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor drd3 mutants attenuated modafinil-induced effects. DRD4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the drd1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine DRD4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine drd1 and DRD4 receptors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
89Exp. Mol. Med. 2011 Jan 43: 44-52
PMID21178390
TitleAssociations between DRDs and schizophrenia in a Korean population: multi-stage association analyses.
AbstractThe dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
90Behav Brain Funct 2011 -1 7: 43
PMID21981786
TitleThe genetic validation of heterogeneity in schizophrenia.
Abstractschizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.
Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.
No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).
The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
91Mol. Biol. Rep. 2011 Apr 38: 2569-72
PMID21110120
TitleIs the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia?
Abstractschizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
92Mol. Biol. Rep. 2011 Apr 38: 2569-72
PMID21110120
TitleIs the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia?
Abstractschizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
93Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Apr 37: 62-75
PMID22203087
TitleDopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration.
AbstractThis study aimed to: 1) replicate previously reported associations between dopamine D4 receptor gene (DRD4) polymorphisms and antipsychotic (AP) response in a clozapine (CLZ) response sample; and 2) explore possible associations of polymorphisms across dopamine D5 receptor gene (DRD5) as well as other DRD4 regions.
DRD4 exon III 48-bp, intron I (G)(n), and 120-bp repeat polymorphisms, and three DRD4 single nucleotide polymorphisms (SNPs); and DRD5 (CA/CT/GT)(n) microsatellite and four DRD5 SNPs were assessed using standard genotyping and statistical procedures.
We report evidence, which does not survive correction for multiple testing, supporting previous DRD4 findings. Findings of interest include the 120-bp 1-copy allele, intron I (G)(n) 142-bp/140-bp genotype, and exon III 4R allele with CLZ response. All DRD5 tests were negative.
Overall, these results suggest a possible minor contribution of DRD4 variants, but not DRD5 variants, towards the AP/CLZ response phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
94PLoS ONE 2012 -1 7: e50970
PMID23226551
TitleAntipsychotic-induced movement disorders in long-stay psychiatric patients and 45 tag SNPs in 7 candidate genes: a prospective study.
AbstractFour types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1).
Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders.
Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained.
The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
95Neurosci. Lett. 2012 Jun 518: 41-4
PMID22569179
TitleRs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese.
AbstractThe dopamine receptor genes have been implicated in the pathogenesis of schizophrenia, but definitive evidence of association is still lacking. To identify whether functional variants of the D2-like receptors (DRD2, DRD3 and DRD4) confer risk of schizophrenia, we conducted a two-stage association study. We firstly examined the SNPs in functional genomic regions, such as mRNA splicing, protein coding and the promoter regions in DRD2, DRD3 and DRD4, respectively, for association in 289 Han Chinese cases with schizophrenia and 367 healthy controls and then further analyzed the significantly associated single nucleotide polymorphisms (SNPs) with this disorder in an additional Han Chinese sample consisted of 1351 cases and 1640 control subjects. In the first stage, the chi-square test (?(2)) showed disease association for rs1076560 in DRD2 (p=0.040 for allelic association and p=0.033 for genotypic association, respectively). However, rs6280 in DRD3 and rs3758653 in DRD4 failed to show either allelic or genotypic association with the illness. The association between rs1076560 and schizophrenia was replicated in the second stage. The rs1076560-T allele, which shifts splicing from the D2 short isoform (D2S) to the D2 long isoform (D2L), was over-presented in the patient group (44%) than in the control group (41%) (?(2)=5.19, p=0.023, OR=1.13, 95% CI=1.02-1.25). Therefore, the rs1076560 variant of DRD2 reliably influences risk of schizophrenia in Han Chinese, although more data are required to elucidate the pathophysiological mechanisms of possessing this risk-conferring variant.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
96Proc. Natl. Acad. Sci. U.S.A. 2012 Aug 109: 13118-23
PMID22822214
TitleNeuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors.
AbstractThe neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal ? oscillations--a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal ? oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases ? oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for ? oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in ? oscillation power. This unique link between D4R and ErbB4 signaling on ? oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and ? oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
97Neurosci. Lett. 2012 Jun 519: 9-13
PMID22543114
TitleDRD4 VNTR polymorphism and age at onset of severe mental illnesses.
AbstractA large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype for genetic investigations of psychiatric disorders. In the present study, the DRD4 VNTR 7 repeat allele (7R) was examined in 477 patients with major psychoses. Age at onset was defined as the age of first psychotic episode for schizophrenia and the age at appearance of first clinically recognized symptoms for the bipolar sample. Our results showed an interaction between sex and DRD4 genotypes among schizophrenia patients (n=203, ?=.213, p=.017). On comparing AAO between carriers and non-carriers of the 7R, we observed that females with 7R present had later onset (p=.021). The effect was not observed for males. In the sample with bipolar disorder, we observed significant association between DRD4 7R-genotype and AAO (n=274, ?=-.148, p=.012). No interaction was observed between sex and genotypic groups of the bipolar sample. The 7R was associated with early onset of the bipolar illness (p=.028). In summary, our results suggest that the 7R is associated with AAO in both schizophrenia and bipolar disorders. The effect was observed across both sexes in bipolar disorder, but specifically in females for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
98Psychiatr. Genet. 2013 Oct 23: 183-7
PMID23851595
TitleAnalysis of association between dopamine receptor genes' methylation and their expression profile with the risk of schizophrenia.
Abstractschizophrenia (SCZ) is a type of psychotic disorder that affects ~1% of the population. Dopamine is one of the major neurotransmitters in the brain and its receptors are associated with a number of psychotic disorders, including SCZ. The aims of the present study were to analyze methylation and the expression profile of dopamine receptor DRD1, DRD2, DRD4, and DRD5 genes in patients with SCZ.
Promoter methylation of DRD1, DRD2, DRD4, and DRD5 genes was assayed by a methylation-specific PCR in blood samples obtained from 80 SCZ cases and 71 healthy controls. Also, we investigated DRD1, DRD2, DRD4, and DRD5 mRNA levels using real-time reverse transcription PCR in 34 blood samples of healthy controls and cases.
Promoter methylation of DRD4, DRD5, and DRD2 genes was statistically different in cases compared with healthy controls. The mRNA expression level results also showed statistically significant differences (P<0.0001) between cases and healthy controls for the DRD2, DRD4, and DRD5 genes, but not for DRD1.
Analyses of DRD genes' methylation have highlighted the fact that the DRD gene network, overall, is actively involved in the increased risk of SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
99Schizophr Bull 2013 Jul 39: 766-75
PMID23512949
TitleClinical and molecular genetics of psychotic depression.
AbstractThis review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of "psychotic depression." Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
100Eur. Psychiatry 2014 Jun 29: 304-6
PMID24630741
TitlePsychosis-proneness correlates with expression levels of dopaminergic genes.
AbstractPsychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
101Neuroscience 2014 Feb 260: 265-75
PMID24345476
TitleLack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus.
AbstractBrain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of psychiatric conditions including major depression and schizophrenia. Mice lacking activity-driven BDNF expression through promoter IV (knock-in promoter IV: KIV) exhibit depression-like behavior, inflexible learning, and impaired response inhibition. Monoamine systems (serotonin, dopamine, and noradrenaline) are suggested to be involved in depression and schizophrenia since many of the current antidepressants and antipsychotics increase the brain levels of monoamines and/or act on monoamine receptors. To elucidate the impact of activity-driven BDNF on the monoamine systems, we examined mRNA levels for 30 monoamine-related genes, including receptors, transporters, and synthesizing enzymes, in KIV and control wild-type mice by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). mRNA levels were measured in the frontal cortex and hippocampus, which are regions related to depression and schizophrenia and where promoter IV is active. The frontal cortex of KIV mice showed reduced levels of mRNA expression for serotonin receptors 1b, 2a, and 5b (5HTR1b, 5HTR2a, 5HTR5b), dopamine D2 receptors (DRD2), and adrenergic receptors alpha 1a and 1d (AdR?1a and AdR?1b), but increased levels for serotonin synthesizing enzyme, tryptophan hydroxylase (TPH), and dopamine D4 receptor (DRD4) when compared to control wild-type mice. The hippocampus of KIV mice showed decreased levels of 5HTR5b. Our results provide causal evidence that lack of promoter IV-driven BDNF disturbs expression of monoaminergic genes in the frontal cortex and hippocampus. These disturbed expression changes in the monoamine systems may mediate the depression- and schizophrenia-like behavior of KIV mice. Our results also suggest that antidepressant and antipsychotic treatments may actually interfere with and normalize the disturbed monoamine systems caused by reduced activity-dependent BDNF, while the treatment responses to these drugs may differ in the subject with reduced BDNF levels caused by stress and lack of neuronal activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
102Psychiatr. Genet. 2014 Dec 24: 273-6
PMID25304228
TitleGenetic association between the DRD4 promoter polymorphism and clozapine-induced sialorrhea.
AbstractThe use of clozapine, an effective antipsychotic drug used in treatment-resistant schizophrenia, is associated with adverse effects. Sialorrhea is one such effect, which can be distressing for many patients. Studies on the pharmacogenetics of the adverse effects of clozapine are limited. The aim of the present study was to determine whether clozapine-induced sialorrhea is associated with a 120 base-pairs (bp) tandem duplication polymorphism in the dopamine receptor subtype D4 (DRD4) gene. Ninety-five patients, mean age 35.439.43 years, with treatment-resistant schizophrenia and on clozapine were included in the study. Development of sialorrhea in response to the drug, as manifested by drooling of saliva, was documented in 45 (47.4%) patients. Genotyping of the patients was carried out to detect the presence of the polymorphism of interest. Clozapine-induced sialorrhea was found to be associated significantly with the 120-bp duplication in DRD4. The association was found to fit a log-additive model with an odds ratio of 2.95 (95% confidence interval 1.51-5.75; P=0.0006). Thus, the presence of the 120-bp duplication in DRD4 appears to confer a risk for sialorrhea in response to clozapine therapy. The underlying pathophysiology and clinical significance of this phenomenon warrant further investigation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
103PLoS ONE 2014 -1 9: e101784
PMID25010186
TitleDissociable genetic contributions to error processing: a multimodal neuroimaging study.
AbstractNeuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.
We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.
We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.
DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
104PLoS ONE 2014 -1 9: e89128
PMID24586542
TitleMale-specific association between dopamine receptor D4 gene methylation and schizophrenia.
AbstractThe goal of our study was to investigate whether DRD4 gene DNA methylation played an important role in the susceptibility of Han Chinese SCZ.
Using the bisulphite pyrosequencing technology, DNA methylation levels of 6 CpG dinucleotides in DRD4 CpG island were measured among 30 paranoid SCZ patients, 30 undifferentiated SCZ patients, and 30 age- and gender-matched healthy controls.
Strong correlation was observed among the six CpG sites (r>0.5, P<0.01), thus average methylation levels were applied thereafter. Our results indicated that there was a significant association between DRD4 methylation and the risk of SCZ (P?=?0.003), although there was no significant difference in DRD4 methylation between the two SCZ subtypes (P?=?0.670). A breakdown analysis by gender showed that the significant association of DRD4 methylation and SCZ was driven by males (P<0.001) but not by females (P?=?0.835). DRD4 methylation was significantly associated with p300 in male SCZ patients (r?=?-0.543, P?=?0.005) but not in female SCZ patients (r?=?0.110, P?=?0.599). Moreover, receiver operating characteristic (ROC) curves showed DRD4 methylation was able to predict the status of SCZ in males [area under curve (AUC)?=?0.832, P?=?0.002] but not in females (AUC?=?0.483, P?=?0.876). Finally, a further expression experiment showed that DRD4 methylation in the gene body was positively associated with gene expression, although the exact mechanism of gene regulation remained unknown for this interesting DRD4 methylation.
The gender disparity in the DRD4 DNA methylation provides novel insights into the pathogenesis of SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
105Neuroscience 2014 Mar 262: 176-89
PMID24406443
TitleFunctional characterization of rare variants in human dopamine receptor D4 gene by genotype-phenotype correlations.
AbstractNext generation sequencing technologies have facilitated a notable shift from common disease common variant hypothesis to common disease rare variant, as also witnessed in recent literature on schizophrenia. Dopamine receptor D4 (DRD4), a G-protein-coupled receptor is associated with psychiatric disorders and has high affinity for atypical antipsychotic clozapine. We investigated the functional role of rare genetic variants in DRD4 which may have implications for translational medicine. CHO-K1 cells independently expressing four rare non-synonymous variants of DRD4 namely R237L, A281P, S284G located in the third cytosolic loop and V194G, located in the fifth transmembrane domain were generated. Their genotype-phenotype correlations were evaluated using [H]spiperone binding, G-protein activation and molecular dynamics-simulation studies. A281P and S284G were functionally similar to wildtype (WT). With R237L, potency of dopamine and quinpirole reduced ?sixfold and threefold respectively compared to WT; [H]spiperone binding studies showed a reduction in total number of binding sites (?40%) but not binding affinity, in silico docking studies revealed that binding of both dopamine and spiperone to R237L was structurally similar to WT. Of note, V194G variant failed to inhibit forskolin-stimulated adenylate cyclase activity and phosphorylate extracellular signal-regulated kinase; showed significant reduction in binding affinity (K(d)=2.16 nM) and total number of binding sites (?66%) compared to WT in [H]spiperone binding studies; and ligand docking studies showed that binding of dopamine and spiperone is superficial due to probable structural alteration. Transmembrane variant V194G in DRD4.4 results in functional alteration warranting continuing functional analysis of rare variants.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
106Eur. Psychiatry 2014 Jun 29: 304-6
PMID24630741
TitlePsychosis-proneness correlates with expression levels of dopaminergic genes.
AbstractPsychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
107Psychiatr. Genet. 2015 Jun 25: 135-6
PMID25714447
TitleAssociation of GRIN1, ABCB1, and DRD4 genes and response to antipsychotic drug treatment in schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
108J Psychiatr Res 2015 Jan 60: 1-13
PMID25287955
TitleSpecific and common genes implicated across major mental disorders: a review of meta-analysis studies.
AbstractMajor efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
109Prilozi 2015 -1 36: 53-67
PMID26076775
TitlePharmacogenetics and antipsychotic treatment response.
Abstract(Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
110Prilozi 2015 -1 36: 53-67
PMID26076775
TitlePharmacogenetics and antipsychotic treatment response.
Abstract(Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal
111Neurosci. Lett. 2016 Apr 619: 126-30
PMID26957229
TitleAssociations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis.
AbstractDopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal