Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.
Mol Psychiatry 1999 Nov
PMID:The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder. 1057 41

NESP55, a novel member of the chromogranins, was originally implicated as a precursor of a peptide LSAL with 5-HT1B receptor antagonist activity. In humans, NESP55 (MIM 139320) is encoded by an alternative transcript of GNAS1, the gene encoding the guanine nucleotide-binding alpha subunit of G(S). As a result of the potential relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence using genomic DNA pools from autistic disorder, obsessive-compulsive disorder (OCD) probands and control subjects. Six single nucleotide polymorphisms (SNPs) were identified and the allele frequencies of those SNPs were determined. In addition, a 24-bp in-frame deletion in the coding region was found in one of the OCD probands. To further investigate its pattern of inheritance and the relevance to studied phenotypes, we genotyped 123 total subjects from autism, OCD and attention deficit hyperactivity disorder (ADHD) families. The deletion was detected only in one OCD family and followed Mendelian inheritance. All subjects with the deletion were heterozygous. However, there are no specific behavioural or physical alterations in the subjects with this deletion variant. The physiological role of NESP55 in serotoninergic neurotransmission as well as the effect of the deletion on its function should be evaluated in future studies.
Mol Cell Probes 2000 Jun
PMID:Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1. 1086 Jul 17

The search for genetic factors predisposing to Attention Deficit Hyperactivity Disorder (ADHD) has focused on genes that regulate dopaminergic pathways such as dopamine receptors and enzymes that regulate levels of dopamine in the synapse. There have been several reports of association between ADHD and polymorphic variants within or near DRD4, DRD5, DAT1, DBH and COMT. In this study we set out to investigate specific alleles of DRD4 and DRD5, previously reported to be associated with ADHD, in a sample of Turkish children with DSM-IV ADHD children, as well as their relation to methylphenidate response and dimensional measures of symptom domains. One hundred and four independent trios and seven dyads were analysed using the transmission disequilibrium test (TDT). We found increased transmission of the DRD4 7-repeat allele (DRD4*7) (TDT chi2 = 2.79, P = 0.047). Given that we were testing specific a priori hypotheses regarding the associated alleles, we have used one-tailed P-values throughout. There was evidence of an interaction with methlyphenidate (MPH) response and analysis of the sample excluding non-responders revealed more significant evidence for the association (TDT chi2 = 4.48, P = 0.017). We also detected a trend for linkage and association in the DRD5 polymorphism (TDT chi2 = 2. 38, P = 0.06). Similar findings were obtained in relation to MPH response as analysis of MPH responders alone gave rise to a more significant association than that of the group as a whole (TDT chi2 = 4.9, P = 0.013). t-Test and logistic regression TDT analyses of DRD4*7 transmission with respect to dimensional rating scales of hyperactivity and impulsivity showed an inverse relation suggesting that in this sample DRD4*7 is associated with a lower level of ADHD symptomatology. While this may be due to stratification along a dimension of severity such that severe cases belong to a more extreme group with other specific genetic and environmental causes, similar to the model for low cognitive ability, it is more likely the result of a chance selection bias in this sample.
Mol Psychiatry 2000 Jul
PMID:Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. 1088 50

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3' untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.
Mol Psychiatry 2000 Sep
PMID:A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder. 1103 86

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5' transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed.
Mol Psychiatry 2000 Sep
PMID:Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). 1103 87

A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD.
Mol Psychiatry 2000 Sep
PMID:Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). 1103 88

The human dopamine transporter (DAT) gene contains a variable number tandem repeat (VNTR; 40 bases/3 to >11 repeats) in the 3'-untranslated region (3'-UTR), resulting in multiple alleles categorized by length. The 10-copy allele has been associated with attention deficit hyperactivity disorder (ADHD), yet it accounts for only a small proportion of symptom variance. We investigated whether the rhesus monkey DAT gene contains a repeat sequence similar to the human and whether this region differs in the five most hyperactive and the five most sedate animals selected from a behaviorally characterized cohort (n = 22). A fixed number tandem repeat (FNTR; 39 bases/12 repeats) was observed in all animals. Accordingly, this FNTR is unbefitting an association of DAT transcript length with hyperactivity. However, sequence analysis revealed potential single nucleotide polymorphisms (SNPs), one of which affects a Bst1107I restriction site. We screened the entire cohort, confirmed that all the rhesus monkeys had repeat regions of the same length, and demonstrated that digestion with Bst1107I was sufficient to distinguish two distinct FNTR alleles. Bst1107I genotype was suggestive but not predictive of hyperactive behavior. Based on these data, we speculated that SNPs may exist in human DAT VNTR alleles. To support this hypothesis, we cloned a portion of a novel 10-repeat allele from the human gene containing an SNP that abolishes a DraI restriction site. We conclude that SNPs create a diversity of DAT alleles between individuals that may be greater than previously identified based solely on the length of the VNTR region, and that alleles of specific sequence may contribute to dopamine-related disorders.
Mol Psychiatry 2001 Jan
PMID:Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates: implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders. 1124 85

alpha(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.
Mol Psychiatry 2001 Mar
PMID:An in-frame deletion in the alpha(2C) adrenergic receptor is common in African--Americans. 1131 18

Dopa decarboxylase (DDC) is an enzyme which catalyses the decarboxylation of both dopa to dopamine and L-5 hydroxytryptophan to serotonin. Both catecholamines are major neurotransmitters of the mammalian nervous system. It has been suggested that genes involved in the dopaminergic system play a primary role in predisposing to attention deficit hyperactivity disorder (ADHD). In this study, the 4-bp insertion/deletion variant mapped to the first neuronally expressed exon 1 at the dopa decarboxylase gene and two microsatellite markers flanking the gene were investigated for possible association with ADHD. Using HHRR, we observed an increased transmission (though not significant) of the 4-bp insertion (allele 1) to ADHD cases (chi(2) = 2.72, P = 0.1, RR = 1.25). However marginally significant excess transmission of allele 10 (213 bp) of the 3' microsatellite D7S2422 ( approximately 0.75 cM distal to dopa decarboxylase gene) was found (chi(2) = 4.2, P = 0.04, RR=1.48). Interestingly, a haplotype containing both alleles is transmitted more frequently (chi(2)= 5, P = 0.025). Analysing data by the sex of transmitting parent showed a greater relative risk for paternal transmission of the 4-bp insertion allele and allele 10 of the D7S2422 (RR = 1.48 and 1.63 respectively). This provides preliminary evidence that this locus or a closely mapped DNA variant may be involved in the genetic susceptibility to ADHD. However, further studies are required to either confirm or refute these observations.
Mol Psychiatry 2001 Jul
PMID:Dopa decarboxylase gene polymorphisms and attention deficit hyperactivity disorder (ADHD): no evidence for association in the Irish population. 1144 26

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein. To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the gene, five that support an association and three against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT). Results from the UK (chi(2) = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (chi(2) = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (chi(2) = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (chi(2) = 22.64, df = 8, P = 0.004).
Mol Psychiatry 2001 Jul
PMID:Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples. 1144 27


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