| 1 | Psychiatr. Genet. 2007 Jun 17: 159-63 |
|---|---|
| PMID | 17417059 |
| Title | A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate. |
| Abstract | Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Psychiatr. Genet. 2007 Jun 17: 159-63 |
| PMID | 17417059 |
| Title | A dopamine D2 receptor gene-related polymorphism is associated with schizophrenia in a Spanish population isolate. |
| Abstract | Numerous lines of evidence have highlighted the involvement of the dopamine system in the pathophysiology of schizophrenia. Association studies of dopaminergic genes such as the dopamine D2 receptor gene (DRD2), however, have produced contradictory results. To test the hypothesis that DRD2 polymorphisms are associated with schizophrenia, we investigated two DRD2-related polymorphisms (TaqI A1/A2 or rs1800497 and -141-C Ins/Del or rs1799732) in a Spanish population isolate from northern Spain consisting of 165 controls and 119 patients with schizophrenia. The TaqI A1 allele was less frequent in schizophrenic patients than in controls (P=0.002). A similar association was found for the TaqI A2/A2 genotype (P=0.0003). No association was found for the DRD2 -141-C Ins/Del polymorphism. The strong association between a potentially functional polymorphism, downstream of the DRD2 gene and schizophrenia, suggests that the direct or indirect functional effects of this polymorphism, acting on either the ANKK1 or DRD2 genes, may play a role in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurotox Res 2009 Jul 16: 50-9 |
| PMID | 19526298 |
| Title | The ANKK1 kinase gene and psychiatric disorders. |
| Abstract | The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Neurotox Res 2009 Jul 16: 50-9 |
| PMID | 19526298 |
| Title | The ANKK1 kinase gene and psychiatric disorders. |
| Abstract | The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychiatr. Genet. 2009 Oct 19: 259-68 |
| PMID | 19512960 |
| Title | Genetic diagnostics of functional variants of the human dopamine D2 receptor gene. |
| Abstract | The importance of dopamine D2 receptors (DRD2) for central nervous dopaminergic signalling makes variants in the DRD2 gene potential modulators of the risk or course of various behavioural, psychiatric or neurologic diseases (e.g. addiction, schizophrenia, Parkinson's disease). We developed Pyrosequencing genetic screening assays for single nucleotide polymorphisms spanning the whole range of the DRD2 gene locus up to the functionally related ankyrin repeat and kinase domain containing 1 gene (ANKK1) located at approximately 10 kb downstream of DRD2. Assays for 11 genetic variants with reported functional association were developed in DNA samples from 300 unrelated healthy Caucasians and validated by independent conventional sequencing. In all DNA samples the DRD2/ANKK1 genetic variants were identified correctly as verified by the control samples. The observed frequencies of homozygous, heterozygous and noncarriers of the minor alleles were in agreement with the Hardy-Weinberg equilibrium. Observed minor allele frequencies were DRD2 rs12364283T>C: 6.5%, rs1799978A>G: 4.8%, rs1799732C del: 14.2%, rs4648317C>T: 12.8%, rs1079597G>A: 13.8%, rs1076560G>T: 14.5%, rs1800496C>T: 0.2%, rs1801028C>G: 3.0%, rs6275C>T: 32.7%, rs6277C>T: 53.0% and ANKK1 rs1800497C>T: 17.5%. The presently developed Pyrosequencing assays are provided to facilitate further research toward personalized approaches to pathophysiological conditions involving behavioural, psychiatric and neurologic disorders including addiction, schizophrenia and Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | J Psychiatr Res 2009 Mar 43: 600-6 |
| PMID | 18926547 |
| Title | Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients. |
| Abstract | Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J Psychiatr Res 2009 Mar 43: 600-6 |
| PMID | 18926547 |
| Title | Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients. |
| Abstract | Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | J. Neurosci. 2010 Oct 30: 14205-12 |
| PMID | 20962241 |
| Title | Frontostriatal involvement in task switching depends on genetic differences in d2 receptor density. |
| Abstract | Recent studies suggest an association of dopamine D2 receptor (DRD2) availability with flexibility in reward-based learning. We extend these results by demonstrating an association of genetically based differences in DRD2 density with the ability to intentionally switch between nonrewarded tasks: noncarriers of the A1 allele of the DRD2/ANKK1-TaqIa polymorphism, associated with higher DRD2 density, show increased task-switching costs, increased prefrontal switching activity in the inferior frontal junction area, and increased functional connectivity in dorsal frontostriatal circuits, relative to A1 allele carriers. A DRD2 haplotype analysis in the same sample confirmed these results, indicating an association between high D2 density and increased task-switching effort. Our results provide evidence that converges with that from association studies relating increased D2 density to deficits in cognitive flexibility in schizophrenia. We suggest that individual differences in striatal D2 signaling in healthy humans modulate goal-directed gating to prefrontal cortex, thus leading to individual differences in switching intentionally to newly relevant behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Apr 34: 492-9 |
| PMID | 20138949 |
| Title | A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes. |
| Abstract | The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1. We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1. Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p=0.01, Odds Ratio=1.5, 95% Confidence Interval=1.1-2.2), and the intergenic rs2242592 (p=2.10(-4), OR=1.8, 95%CI=1.3-2.5). A significant SNP-SNP interaction was also found (p<10(-5), OR=2.0, 95%CI=1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage. Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Alcohol. Clin. Exp. Res. 2011 May 35: 963-75 |
| PMID | 21314694 |
| Title | Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. |
| Abstract | While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Int. J. Neuropsychopharmacol. 2012 Nov 15: 1427-40 |
| PMID | 22244514 |
| Title | Sensorimotor gating and D2 receptor signalling: evidence from a molecular genetic approach. |
| Abstract | Converging evidence from pharmacological investigations, genetic association studies and schizophrenia research indicates an important influence of the dopamine system on sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response. In particular, D2 receptor agonists have been shown to disrupt PPI in humans and rodents. In the present study, we investigated the associations of two functional DRD2 related single nucleotide polymorphisms (rs4648317 and rs1800497, the latter also known as DRD2/ANKK1 Taq1A) with PPI in two independent healthy human samples (overall n=197; Munich n=101; London n=96). Taq1A is a prominent marker of striatal D2 receptor signalling and was therefore hypothesized to impact on PPI. In line with our hypothesis, we report here reduced PPI levels in individuals with higher striatal D2 receptor signalling as indicated by the Taq1A genotype. Meta-analysis across both samples confirmed this finding. In contrast, an association between rs4648317 and PPI found in the Munich sample could not be confirmed in the London sample. Overall, the present study helps to bridge the gap between pharmacological manipulations of PPI and molecular genetics of the dopaminergic system. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | J Clin Psychopharmacol 2012 Aug 32: 441-8 |
| PMID | 22722500 |
| Title | Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. |
| Abstract | Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | J Clin Psychiatry 2012 Aug 73: 1077-86 |
| PMID | 22967772 |
| Title | Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. |
| Abstract | Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Eur Arch Psychiatry Clin Neurosci 2013 Feb 263: 65-74 |
| PMID | 22893251 |
| Title | Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol. |
| Abstract | The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Aug 53: 123-8 |
| PMID | 24704945 |
| Title | Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism. |
| Abstract | Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Oct 165B: 564-71 |
| PMID | 25073965 |
| Title | Identification of ANKK1 rs1800497 variant in schizophrenia: new data and meta-analysis. |
| Abstract | One functional polymorphism (rs1800497) within the ankyrin repeat and kinase domain containing-1 gene (ANKK1) was reported to be associated with schizophrenia, but results among different studies vary and conclusions remain controversial. The present study sought to clarify this potential association among a population of Han Chinese with early onset schizophrenia using a case-control (396 patients and 399 controls) and family based study (103 trios). We then performed a meta-analysis (comprising 11 case-control and 2 family-based studies) based on the present literature. Results of the association study revealed no significant difference in allele and genotype frequencies between the cases and controls, and no significant transmission distortion was detected. Kaplan-Meier survival analysis showed that age at onset in schizophrenia was significantly associated with the rs1800497 polymorphism in female patients, but not in males. Female T allele carriers had a lower age at onset than those without T allele (log rank statistic ?(2)?=?5.16, P?=?0.023; corrected P?=?0.046). Meta-analysis results indicated that rs1800497 is not associated with schizophrenia in the overall population (P?=?0.77 for the case-control studies; P?=?0.06 for the family-based studies). Our results support the hypothesis that rs1800497 polymorphism is likely to have a modifying rather than causative effect on schizophrenia. These findings may represent a significant genetic clue for the etiology of schizophrenia in females, but further investigation is required to clarify the exact role of ANKK1 in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Psychopharmacology (Berl.) 2015 Jan 232: 145-54 |
| PMID | 25096017 |
| Title | Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. |
| Abstract | Type-3 metabotropic glutamate receptor gene (GRM3) single nucleotide polymorphisms (SNPs) have been associated with cognitive performance and prefrontal cortex brain activity in chronically treated schizophrenia patients. Whether these SNPs are associated with cognitive and symptom response to antipsychotic therapy has not been extensively evaluated. The aim of the study was to examine pharmacogenetic relationships between GRM3 and selected variants in relevant dopamine genes with changes in spatial working memory and clinical symptoms after treatment. Sixty-one untreated first-episode schizophrenia patients were assessed before and after 6 weeks of antipsychotic pharmacotherapy, primarily consisting of risperidone. Patients' level of cognitive performance on a spatial working memory task was assessed with a translational oculomotor paradigm. Changes after treatment in cognitive and clinical measures were examined in relationship to genetic polymorphisms in the GRM3, COMT, and DRD2/ANKK1 gene regions. Spatial working memory performance worsened after antipsychotic treatment. This worsening was associated with GRM3 rs1468412, with the genetic subgroup of patients known to have altered glutamate activity having greater adverse changes in working memory performance after antipsychotic treatment. Negative symptom improvement was associated with GRM3 rs6465084. There were no pharmacogenetic associations between DRD2/ANKK1 and COMT with working memory changes or symptom response to treatment. These findings suggest important pharmacogenetic relationships between GRM3 variants and changes in cognition and symptom response with exposure to antipsychotics. This information may be useful in identifying patients susceptible to adverse cognitive outcomes associated with antipsychotic treatment and suggest that glutamatergic mechanisms contribute to such effects. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | Biomed Res Int 2015 -1 2015: 821827 |
| PMID | 26114114 |
| Title | Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia. |
| Abstract | Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jan 168B: 1-13 |
| PMID | 25504812 |
| Title | Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. |
| Abstract | The role of dopamine D2 receptor (DRD2) polymorphisms in schizophrenia remains controversial. We performed a meta-analysis to determine whether DRD2 polymorphisms influence the risk of schizophrenia and examined the relationship between rs1799732, rs1801028, and rs1800rs028 an23381d rs1800497 genetic variants and the etiology of schizophrenia. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, and cumulative meta-analysis were performed. A total of 76 studies with 16096 cases and 18965 controls were included. Specifically, 24 studies with 6075 cases and 6643 controls involved rs1799732, 36 studies with 8043 cases and 10194 controls involved rs1801028 and 16 studies with 1978 cases and 2128 controls involved rs1800497. No significant associations were observed between rs1799732 and rs1800rs732 and rs1800497 and schizophrenia. The rs1801028 locus was associated with schizophrenia, with a pooled OR of 1.221 (95% CI = 1.037-1.438, P = 0.016). This meta-analysis indicates that the rs1801028 locus may be associated with schizophrenia. These data provide possible references for future case-control studies related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Synapse 2016 May -1: -1 |
| PMID | 27241797 |
| Title | Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. |
| Abstract | In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. This article is protected by copyright. All rights reserved. |
| SCZ Keywords | schizophrenia, schizophrenic |