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PubMed1994

The genes encoding the glutamate receptor subunits KA1 and KA2 (GRIK4 and GRIK5) are located on separate chromosomes in human, mouse, and rat.

The chromosomal localization of the human and rat genes encoding the kainate-preferring glutamate receptor subunits KA1 and KA2 (GRIK4 and GRIK5, respectively) was determined by Southern analysis of rat x mouse and human x mouse somatic cell hybrid panels and by fluorescence in situ hybridization. The localization of the mouse genes (Grik4 and Grik5) was established by interspecific backcross mapping. GRIK4 and GRIK5 are located on separate chromosomes (Chrs) in all species. GRIK4 mapped to human Chr 11q22.3, mouse Chr 9, and rat Chr 8. GRIK5 mapped to human Chr 19q13.2, mouse Chr 7, and rat Chr 1. The genes encoding the (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-preferring subunit GluR4, or GluRD (GRIA4), the neural cell adhesion molecule (NCAM), the D2 dopamine receptor (DRD2), and the Thy-1 cell surface antigen (THY1) have all been previously mapped to the human Chr 11q22 region. The mapping of the human GRIK4 and GRIK5 genes confirms and extends the relationship between human Chr 11 and mouse Chr 9 and also human Chr 19 and mouse Chr 7. GRIK4 is the fifth gene shared by human Chr 11 and rat Chr 8, whereas GRIK5 is 1 out of the 12 genes that are located on both human Chr 19 and rat Chr 1. Our data extend the conserved synteny established between certain human, mouse, and rat Chrs.

Animals↗
PubMed2005

Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis.

Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.

Animals↗
PubMed1996

DNA workbench: a database package to manage regional physical mapping.

DNA Workbench (DW) is a client-server database to manage physical mapping data that will form the basis for sequencing and efforts in biologically interesting regions of a chromosome. DW draws maps at different levels of resolution in either of two modes: proportional, when the sizes of objects and the physical distances between them are known accurately or approximately, and nonproportional, when most physical distance information in a region is not available, but order information is. DW interacts with the user primarily through the map graphic. Selection of individual objects on the graphic lets the user inspect and modify the underlying data. DW also manages dependency tracking between map objects and has a rudimentary form of version control. It is currently used to manage information on the DRD2 region on chromosome 11, and on the HOX region of chromosome 17.

Chromosome Mapping↗
PubMed2006

Study of dopamine receptors genes polymorphisms in bipolar patients with comorbid alcohol abuse.

UNLABELLED: Alcoholism is present in approximately 40-60% of bipolar patients. This comorbidity between bipolar disorder and alcoholism is high and may result from existence of common genetic factors for the two disorders. In both disorders, dysregulation of the dopaminergic neurotransmission had been implicated. Association analyses revealed several candidate genes acting in the dopaminergic pathway and polymorphisms in those genes that might be associated with both disorders. AIM: The aim of this study was to analyse possible relationship between polymorphisms in the dopaminergic pathway genes (one SNP for each dopamine receptor gene 1-4) and alcohol abuse comorbidity in bipolar patients. METHODS: We analysed 317 patients with bipolar disorder. In this group, 42 patients were diagnosed with alcohol abuse. The diagnosis was made for each patient by at least two psychiatrists, using structured clinical interviews for DSM-IV Axis I disorders (SCID). The control group consisted of 350 subjects. We performed RFLP analysis of polymorphisms in four genes: DRD1, DRD2, DRD3, and DRD4. RESULTS: We have not found association of any of the analysed polymorphisms in the dopamine genes in the group of bipolar patients with comorbid alcohol abuse as compared to the control group. In the male group of bipolar patients with comorbid alcohol abuse, we also have not observed any significant differences between the patients and the control subjects. CONCLUSION: Our findings suggest that the analysed polymorphisms of the dopamine genes polymorphisms may not be involved in the shared genetic vulnerability to both, bipolar disorder, and alcohol abuse.

Adult↗
PubMed2026

Evaluation of epistasis detection methods for quantitative phenotypes.

MOTIVATION: Epistasis, or genetic interaction, plays a crucial role in shaping complex traits and has been increasingly recognized for its widespread influence in genetic architectures. While epistasis detection has been extensively evaluated in case-control studies, its performance with quantitative phenotypes remains comparatively understudied. RESULTS: We identified and evaluated six epistasis detection methods applicable to quantitative trait analysis: EpiSNP, Matrix Epistasis, MIDESP, PLINK Epistasis, QMDR, and REMMA. Using the EpiGEN simulator, we generated synthetic datasets modeling four classes of pairwise SNP interactions-dominant, multiplicative, recessive, and XOR. We also assessed BOOST and MDR algorithms using discretized (case-control) versions of the same datasets. Performance varied notably by interaction type: REMMA achieved the highest overall detection rate (55%), particularly excelling with dominant interactions (100%). MDR excelled with multiplicative (57%) and XOR (69%) interactions. Meanwhile, EpiSNP attained the best performance for recessive interactions (67%). All methods except BOOST produced F1 scores below 0.05 for most interaction types. We further evaluated the methods using a real-world dataset. When applied to the Adolescent Brain Cognitive Development dataset to analyse the externalizing behavior phenotype, both PLINK Epistasis and PLINK BOOST identified SNPs within the DRD2 and DRD4 genes, consistent with previously reported genetic associations. Given the variability in tool performance across interaction types, no single method provides optimal detection across all scenarios. Leveraging multiple detection algorithms may therefore yield more comprehensive insights into epistatic effects in quantitative trait analyses. AVAILABILITY AND IMPLEMENTATION: All relevant code and simulated datasets can be found at github.com/staslist/Epistasis_Review repository.

Epistasis, Genetic↗
PubMed2005

Accurate genotyping from paraffin-embedded normal tissue adjacent to breast cancer.

Genetic polymorphism analysis for disease risk is widely used in epidemiology studies; blood or oral cavity cells are the most widely used source of DNA. However, these types of samples are not always available, particularly for studies that were conducted years ago. An alternative potential source of patient DNA exists in the form of paraffin-embedded normal tissue adjacent to tumor samples, which are collected and stored routinely for clinical use. The use of such samples can be conceptually problematic, however, due to the presence of field cancerization in the surrounding normal tissue, with the possible presence of chromosomal loss. Specifically, loss of heterozygosity (LOH) might bias the genotyping results and cause genotype misclassification. However, field cancerization and LOH might not be an issue because LOH is not easily found unless there is careful microdissection of only tumor cells (leaving stromal, inflammatory and fat cells), for example, laser-capture microdissection. In this study, we set out to determine the degree of genotype misclassification from normal tissues adjacent to tumors, if any, by comparing these results with blood genotyping. We examined samples from 106 subjects with breast cancer, analyzing five different genotypes selected from regions commonly known to have LOH in breast cancer. These genotypes were methylenetetrahydrofolate reductase (MTHFR), oxoguanosine glycosylase 1 (hOGG1), dopamine beta-hydroxylase (DBH), dopamine receptor D2 (DRD2) and NAD(P)H dehydrogenase quinone 1 (NQO1), conducted by using real-time PCR and TaqMan genotyping analyses. We found that among these five genotypes and 106 comparisons, there was a 100% concordance for genotyping from normal tissue adjacent to tumor and from blood. Our findings indicate that the use of adjacent normal tissues provides accurate genotyping results with high specificity. Although this study only used breast tumor samples, and may be applicable only to breast cancer studies, we expect the results to be applicable to other types of cancers also.

Biopsy↗
PubMed1994

Genetics of alcohol misuse.

Family, twin, and adoption studies demonstrate the genetic contribution to alcoholism but also confirm an important environmental component. The current rapid developments in genetics are providing candidate genes that can be assessed for a role in alcoholism, and a reported association with the DRD2 receptor gene is still being examined. Alcoholism is a complex behaviour which may be more amenable to genetic studies when dissected into its constituent parts. It is probable that multiple genes contribute to the genetic vulnerability to alcoholism and, hopefully, the effect of some will be of sufficient size so that they can be identified. Identification of these vulnerability factors will allow targeting of preventative efforts but before genetic tests are used clinically the full ethical implications will need to be considered carefully.

Adoption↗
PubMed1998

Dopamine markers and general cognitive ability.

Because general cognitive ability (g) is among the most heritable behavioural traits, it is a reasonable target for a search for quantitative trait loci (QTLs). We used a selected-extremes design to test candidate genes for allelic association with g. Polymorphisms in four genes in the dopamine system (DRD2, DRD3, DRD4, DAT1) were genotyped for 51 high g children with IQ scores > 130 and for 51 average g control children. No significant allelic or genotypic differences were found between the high g and average g groups for these markers of the dopamine system, even though the selected-extremes design provides power to detect QTL associations that involve a relative risk of about 1.5.

Adolescent↗
PubMed1999

Association of the dopamine transporter gene (DAT1) with poor methylphenidate response.

OBJECTIVE: This study attempted to relate the alleles of the D2 (DRD2), D4 (DRD4), and dopamine transporter (DAT1) genes to the behavioral outcome of methylphenidate therapy. METHOD: African-American children with attention-deficit hyperactivity disorder were treated with methylphenidate in doses not in excess of 60 mg/day. The dosage was increased until behavioral change was achieved, using a decrement in scores of less than or equal to 1 on a commonly used rating scale or until the maximum tolerated dose was achieved. Blood samples were obtained at that point, and genotypes for polymorphism at the respective genes were identified. RESULTS: Genotypes were then tested by chi 2 to assess the significance of any association with drug response. Only the dopamine transporter gene was found to be significant. Homozygosity of the 10-repeat allele was found to characterize nonresponse to methylphenidate therapy (p = .008). CONCLUSIONS: While the results suggest that alleles of the dopamine transporter gene play a role in methylphenidate response, replication in additional studies is needed.

Alleles↗
PubMed1999

Analysis of neuroleptic binding affinities and potencies for the different human D2 dopamine receptor missense variants.

Neuroleptics, or antipsychotics, are widely used for the treatment of psychotic symptoms such as hallucinations and delusions in schizophrenia and other psychiatric disorders. Pharmacotherapy of these diseases is frequently complicated by a great variability in the clinical response to neuroleptics and by the development of serious and potentially life-threatening side-effects. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatment. The human D2 dopamine receptor (DRD2) gene has three variants predicting the amino acid substitutions Ser311Cys, Pro310Ser and Val96Ala in the receptor protein. We show that several typical and atypical neuroleptics commonly used in the treatment of psychotic disorders have differences in binding affinities and potencies for the D2 dopamine receptor variants. Functional differences between dopamine receptor variants might be related to genetically determined differences in response to neuroleptic treatment.

Animals↗
PubMed1998

Current status of genetic discoveries in migraine: familial hemiplegic migraine and beyond.

Familial hemiplegic migraine (FHM) has been related to mutations in a brain calcium channel gene among Chr19p linked FHM families. Subsequent genetic Studies in different FHM families showed that additional causative genes must reside in other regions of the genome, including the long arm of Chromosome 1. Parallel discoveries in mouse mutants involving ion channel genes have also accelerated our understanding of the spectrum and functional significance of the CNS-related ion channel disorders. These studies have clear implications for migraine, epilepsy, and ataxia. An association study was suggested that other 'susceptibility' genes like the dopamine DRD2 receptor will be important in characterizing the genetic components of the larger, heterogeneous group of migraine disorders.

Animals↗
PubMed1994

No major role for the dopamine D2 receptor Ser-->Cys311 mutation in schizophrenia.

A new structural polymorphism (Ser311/Cys311) in the dopamine D2 receptor (DRD2) gene has recently been reported to be associated with schizophrenia, particularly in patients with a positive family history of schizophrenia (Arinimi et al., 1994). However these findings remain controversial (Asherson et al., 1994; Nanko et al., 1994; Nöthen et al., 1994; Shaikh et al., 1994). Thus we investigated the role of the Cys311 mutation in schizophrenia using both association and family studies. First, we screened for the Cys311 mutation in 113 unrelated Caucasian schizophrenics (mean age 42 +/- 0.6; 34 females and 79 males) including 25 familial cases, and 184 unrelated controls (mean age 49 +/- 0.5, 74 females and 110 males) free of any psychiatric disorders. Diagnoses were ascertained according to DSM-III criteria (Campion et al., 1994). All patients and controls were native to the area of Rouen.

Alleles↗
PubMed1995

Dopamine D1, D2 and D3 receptor genes in alcohol dependence.

Hereditary factors play a substantial role in the etiology of alcohol dependence. Alcohol mediates its reinforcing effects by an activation of the mesolimbic dopamine system. These findings suggest that the genes encoding the dopamine receptor (DR) subtypes represent high-ranking candidates for susceptibility genes to addictive disorders. Our present population-based association study investigated whether sequence variants of the dopamine D1, D2 and D3 receptor genes confer susceptibility to alcohol dependence in 278 alcoholics, and clinically more homogeneous subgroups ascertained through positive family history, early age at onset, delirium, withdrawal seizures and antisocial tendencies. No evidence for an allelic association was found for the PCR-based TaqA RFLP fo the DRD2 gene and a Bsp1286I RFLP of the DRD1 gene. Without correction for multiple testing, we found a significantly increased allele frequency of a common DRD3 gene variant expressing a serine at position 9 in the extracellular N-terminal part of the receptor protein in 55 alcohol-dependent individuals with delirium (chi 2 = 4.1, df = 1, p = 0.042). Further studies have to examine whether this amino acid substitution or a nearby mutation confers genetic susceptibility to at least a subgroup of alcohol-dependent individuals with delirium.

Adult↗
PubMed2003

Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene.

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome (NMS) is unclear, but clinical studies have noted a genetic predisposition. A recent genetic study suggested an association between NMS and the I A polymorphism in the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a larger number of subjects. METHODS: We studied 49 Japanese patients previously diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A polymorphism. RESULTS: The I A1 allele frequency was 0.408 in NMS patients and 0.415 in patients without NMS. No significant differences in allelic or genotypic frequencies were observed between the two groups. CONCLUSIONS: We cannot conclude that the I A polymorphism is associated with development of NMS.

Antipsychotic Agents↗
PubMed2004

Association analysis of dopamine D2-like receptor genes and methamphetamine abuse.

OBJECTIVES: Substance use disorders are familial, and genetic factors explain a substantial degree of their familial aggregation. This study employs an association approach to examine the genetic underpinning of methamphetamine (MAMP) use and MAMP-induced psychosis. METHODS: A total of 416 MAMP abusers from a hospital and a detention center in Taipei were interviewed with the Diagnostic Interview for Genetic Study and the Family Interview for Genetic Study. Genetic polymorphisms of D2-like dopamine receptor genes, DRD2 TaqI A, DRD3 Ser-9-Gly, and DRD4 exon III variable number of tandem repeats, were compared between: (a) MAMP users as a whole and 435 normal controls, and (b) those 154 individuals with MAMP-induced psychosis and the 252 MAMP users with no psychosis. RESULTS: None of the three markers we studied were associated with predisposition to psychosis among the MAMP abusers. The MAMP abusers had a higher (P=0.011) prevalence of the seven-repeat allele of DRD4 than normal controls. CONCLUSIONS: Chance fluctuations in the frequency of rare alleles and ascertainment differences in the case and control samples cannot be ruled out. Therefore, further studies of the seven-repeat allele in MAMP abusers and controls should be performed before an association can be established.

Female↗
PubMed2005

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum.

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post-TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d-amphetamine-induced rotational behavior. Adult male Sprague-Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine-induced rotational behavior was assessed 10 days post-CCI. Fourteen days post-CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V(max) (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury-related changes in vesicular monoamine transporter or D2 receptor expression (DRD2) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.

Animals↗
PubMed2006

Molecular genetics of bipolar disorder.

Bipolar disorder (BPD) is an often devastating illness characterized by extreme mood dysregulation. Although family, twin and adoption studies consistently indicate a strong genetic component, specific genes that contribute to the illness remain unclear. This study gives an overview of linkage studies of BPD, concluding that the regions with the best evidence for linkage include areas on chromosomes 2p, 4p, 4q, 6q, 8q, 11p, 12q, 13q, 16p, 16q, 18p, 18q, 21q, 22q and Xq. Association studies are summarized, which support a possible role for numerous candidate genes in BPD including COMT, DAT, HTR4, DRD4, DRD2, HTR2A, 5-HTT, the G72/G30 complex, DISC1, P2RX7, MAOA and BDNF. Animal models related to bipolar illness are also reviewed, with special attention paid to those with clear genetic implications. We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness.

Animals↗
PubMed2001

Clinical and molecular genetics of ADHD and Tourette syndrome. Two related polygenic disorders.

ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes--DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes--dopamine beta-hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes--TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes--GABRB3; androgen receptor and other genes. This model is consistent with all of the present knowledge about ADHD including (a) the increased frequency of ADHD in the relatives of ADHD probands, (b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, (c) the close relationship to Tourette syndrome (TS), (d) the failure to find the genes for TS using linkage analysis, (e) the brain imaging studies showing hypometabolism of the frontal lobes, (f) the relationship between dopamine D2 receptor density and regional blood flow, (g) the correlation between tics and dopamine D2 receptor density in TS, (h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, (i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, (j) the NE models of ADHD, (k) the failure to explain ADHD on the basis of any single neurotransmitter defect, (l) the response of ADHD to dopamine and alpha 2-adrenergic agonists, (m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.

Attention Deficit Disorder with Hyperactivity↗