Association study between schizophrenia and dopamine D3 receptor gene polymorphism

Crocq et al. [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist.     

Atrial adipofibrosis in a dog

Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients.     

Association between dopamine receptor genes and migraine without aura in a Sardinian sample

BACKGROUND: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. OBJECTIVE: The current report concerns a genetic study to test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. METHODS: For the first time, a family-based association method--the Transmission Disequilibrium Test (TDT)--was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based on the presence of both nausea and yawning immediately before or during the pain phase of migraine. RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients.     

Bladder origin neuroblastoma detected by mass screening

A 5-HT2A receptor promoter polymorphism, -1438G/A, was reported to be significantly increased in patients with anorexia nervosa when compared with controls. In practice, many patients with anorexia nervosa suffer from mood disorders. Furthermore, 5-HT2A receptors are thought to play a role in the etiologies of mood disorders. Thus, we studied the polymorphism in 95 Japanese patients with mood disorders and 106 healthy Japanese controls. The allele frequency for the -1438G/A polymorphism did not differ between the patients and controls. In addition, the genotype frequencies did not differ according to the subdiagnosis, age of onset, family history of psychiatric illness or suicide attempts.     

Absence of anti-envelope antibodies and clearance of hepatitis C virus in a cohort of Irish women infected in 1977

Neuroleptic drugs have a high affinity for the dopamine D2 receptor (DRD2); therefore DRD2 is thought to be a candidate gene for schizophrenia. Arinami et al. have reported a positive association between schizophrenia and the Cys311 variant of the DRD2 gene. We determined the allele frequency of this polymorphism in 78 Okinawan schizophrenic patients and 112 control subjects. The patients and controls did not differ significantly in allele frequencies of Cys311.     

Family issues in the pathogenesis of anorexia nervosa

Factors residing in family systems have been implicated in the pathogenesis of anorexia nervosa. In this paper I critically review literature that bears on this issue: the transmission of anorexia nervosa in families; family stress patterns, personality and psychopathological characteristics of parents, parent-child interactions, and whole family systems. Much additional research is needed to accurately determine the precise nature of such factors and the extent to which they actually contribute to the appearance of this syndrome.     

Association study between the -141C Ins/Del and TaqI A polymorphisms of the dopamine D2 receptor gene and alcoholism

Dopamine D2 receptors have been implicated in the biology of alcohol preference. We examined the -141 C Ins/Del polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) and the DRD2 TaqI A polymorphisms in 209 Japanese alcoholics and 152 age- and sex-matched Japanese controls. The Ins allele was significantly increased in the alcoholics, compared with the controls (p < 0.002, odds ratio = 1.82). The TaqI A1 allele tended to be more frequent in the alcoholics than in the controls (p < 0.04). Linkage disequilibrium between these two polymorphisms was weak (a maximum delta value = 0.13). The -141 C Ins/Del polymorphism may affect the vulnerability for alcoholism presumably through different expression of DRD2 in the Japanese.     

Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease

OBJECTIVE: To examine if selected polymorphisms in the dopamine receptor genes DRD1, DRD2, DRD3, and DRD4 are associated with the presence of psychosis or aggressive behavior in patients with Alzheimer disease (AD). DESIGN: A cohort of patients with AD were longitudinally evaluated for behavioral symptoms and classified with regard to the presence of psychotic symptoms and physical aggression. SETTING: Alzheimer's Disease Research Center. PATIENTS: Two hundred seventy-five elderly outpatients diagnosed as having probable AD. RESULTS: Among white patients, psychosis and aggression were both significantly more frequent in DRD1 B2/B2 homozygotes (P < .02), while psychosis was significantly more frequent in DRD3 1/1 or 2/2 homozygotes (P < .05). The joint risk for psychosis due to the DRD1 and DRD3 polymorphisms exceeded the risks due to either locus alone, suggesting an interaction. Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression. CONCLUSIONS: Genetic variation in DRD1 and DRD3 genes may act to modify the course of AD, predisposing to the development of psychotic or aggressive symptoms. Confirmation in other samples of patients with AD is required.     

Cerebrospinal fluid opioid activity in anorexia nervosa

The authors found higher levels of CSF opioid activity, determined by radioreceptor assay, in patients with anorexia nervosa who were severely underweight than in 1) the same patients after weight restoration and 2) normal controls. Another group of patients who had chronic anorexia nervosa but were not severely underweight had normal levels of CSF opioid activity. Endogenous opioid systems have been shown to be related to eating behavior and metabolic regulation in animals. The association between decreased weight and increased CSF opioid activity observed by the authors may be a compensatory response to weight loss or may be etiologically related to anorexia nervosa.     

Relations between multi-informant assessments of ADHD symptoms, DAT1, and DRD4.

Researchers conducting candidate gene studies of attention-deficit/hyperactivity disorder (ADHD) typically obtain symptom ratings from multiple informants (i.e., mothers, fathers, and teachers) and use a psychologist's best estimate or a simple algorithm, such as taking the highest symptom ratings across informants, to construct diagnostic phenotypes for estimating association. Nonetheless, these methods have never been empirically validated in the context of a molecular genetic study. In the current study, the authors systematically evaluated several methods of operationalizing phenotypes and the resulting evidence for association between ADHD and the candidate genes: dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4). Use of symptom scores as continuous scales in regression analysis suggested that the combination of mother and teacher ratings yielded the strongest evidence for association between hyperactive-impulsive ADHD symptoms and DAT1 and between inattentive ADHD symptoms and DRD4. Teacher ratings alone were sufficient for evaluating the association between inattentive symptoms and DAT1. Further, this regression-based method consistently yielded stronger evidence for association among ADHD symptoms, DAT1, and DRD4 than did three simple algorithms (i.e., the and, or, and averaging rules). The implications of these results for future molecular genetic studies of ADHD are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Serum leptin and body weight in females with anorexia and bulimia nervosa

In this study we hypothesized that there is a correlation between serum leptin levels and body mass indices within patients with anorexia nervosa or bulimia nervosa during a twelve weeks' course of in-patient treatment. We evaluated leptin levels weekly in female in-patients with anorexia (n = 17) or bulimia nervosa (n = 18). Only patients with anorexia nervosa were therapeutically encouraged to gain weight throughout the treatment episode. For the whole cohort, body mass indices and serum leptin levels were highly correlated upon admission (r = 0.89, p < 0.001). The median intra-individual correlation in the anorexia group was higher than in the bulimia group (0.63 and 0.39, respectively). The intra-individual correlations were higher in those anorexia nervosa patients who showed increments of their body mass index within the observation span. This dynamic aspect is important specifically in patients with anorexia nervosa during therapeutically induced weight gain.     

Psychosocial functioning of young adults with cystic fibrosis and their families

BACKGROUND: The psychosocial functioning of adolescents and young adults with cystic fibrosis still living in the parental home was investigated. With its proven genetic aetiology cystic fibrosis is an ideal model with which to assess the impact of a chronic and life threatening disorder on family and individual psychological and social functioning. METHODS: Twenty nine patients with cystic fibrosis and their families were compared with those of 27 patients with anorexia nervosa and 31 well controls. Assessments were made using self reporting, interview, and observational methods. RESULTS: Most patients with cystic fibrosis were in robust psychological health and only differed from their healthy peers in that they were much less likely to be in employment. Mothers of patients with cystic fibrosis or anorexia nervosa were more likely than the mothers of the well group to be emotionally distressed, although this was not so for fathers. Young people in both illness groups were more likely to have parents with high levels of expressed emotion. Most families of patients with cystic fibrosis had good problem solving abilities. CONCLUSIONS: In spite of the burden of illness in cystic fibrosis psychological functioning in many respects matches that of well young people.     

Systematic mutation screening of the estrogen receptor beta gene in probands of different weight extremes: identification of several genetic variants

Estrogens are known to have an inhibitory effect on food intake in rodents and primates. Decreased estrogen levels that are found for instance in menopausal woman and in ovarectomized rodents result in body weight gain. Estrogen can act both in the periphery and in the central nervous system via at least two different estrogen receptors (alpha and beta). We systematically screened the coding region and part of the 5' and 3'regions of the estrogen receptor beta gene (ER beta) in 96 extremely obese children and adolescents, 50 patients with anorexia nervosa (AN), 28 patients with bulimia nervosa (BN), and 25 healthy underweight individuals. We detected five different sequence variants in the ER beta: a) A 21 bp deletion (codons 238 to 244) was detected in two obese probands and an underweight individual. b) An 846G-->A transition leading to a nonconservative amino acid substitution (G-250-S) was found in two obese male probands. Both a) and b) were located within the flexible hinge region between DNA and ligand binding domain. c) For a 1082G-->A polymorphism we found suggestive evidence for an association between the more common 1082G-allele and anorexia nervosa (nominal p=0.04). d) One silent mutation (1421T-->C) was found solely in two obese probands. e) A common variant is located in the 3' nontranslated region at position 1730(A-->G). We did not detect association of this polymorphism to any of the analyzed phenotypes. We conclude that the ER beta harbors several different mutations and polymorphisms, none of which can readily be associated with the phenotypes under study.     

Habit Learning and the Genetics of the Dopamine D? Receptor: Evidence From Patients With Schizophrenia and Healthy Controls.

In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D? receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.     

A study of personality in eating disorders

Some evidence suggests that temperament and personality traits could influence the development and severity of eating disorders. This study was designed to study these aspects. METHODS: 72 patients with DSM-IV eating disorders including 25 anorexia nervosa restricting type, 17 with anorexia nervosa binge eating-purging type and 30 with bulimia nervosa were studied and compared with thirty healthy controls. Personality disorders and temperament were studied with the Eysenck's EPQ, Cloninger's TCI and SCID-II. Impulsive and clinical features were studied with specific rating scales. RESULTS: 61.8% of patients had at least one personality disorder. Avoidant personality disorder was the most commonly diagnosed in anorexia restricting type (25%). Borderline personality disorder was the most frequent in bulimia nervosa and in the binge eating-purging type of anorexia nervosa. Dimensionally, the group of eating disorders presented high scores in neuroticism and low scores in self-directedness. Higher harm avoidance was found in bulimic patients and higher persistence was associated with anorectic patients. Bulimic patients were significantly more impulsive than anorectic and controls. CONCLUSIONS: Temperament and personality traits differ in anorectic and bulimic patients. Bulimic symptoms are linked to impulsive temperament traits and to impulsive personality features. Anorectic symptoms are linked to persistent temperament traits and anxious personality features.     

The GTP cyclohydrolase I gene in Russian families with dopa-responsive dystonia

OBJECTIVE: To search for mutations in the GTP cyclohydrolase I (GCH-I) gene in a set of Russian families with dopa-responsive dystonia (DRD). DESIGN: Six large families with 54 affected family members and 2 patients with sporadic DRD were examined. Mutation screening was performed using single-strand conformation polymorphism analysis followed by direct sequencing of the presumably mutated exons, in patients whose results showed a normal pattern on single-strand conformation polymorphism analysis, the entire coding region of the GCH-I gene was sequenced. RESULTS: Three new heterozygote point mutations located within exons 1, 2, and 4 of the GCH-I gene were identified in 3 families with autosomal-dominant inheritance. All these mutations are predicted to cause amino acid changes in the highly conserved regions of the gene. In patients from 3 other families and in both patients with sporadic DRD, no alterations in the translated portion of the GCH-I gene were observed. CONCLUSIONS: Mutations in the coding region of the GCH-I gene account for a significant fraction (up to half) of the patients with a typical clinical picture of DRD. None of the mutations in the GCH-I gene described so far were detected more than once, which precludes the possibility of creating simple DNA testing procedures for routine clinical practice.     

Are eating disorders culture-bound syndromes? Implications for conceptualizing their etiology.

The authors explore the extent to which eating disorders, specifically anorexia nervosa (AN) and bulimia nervosa (BN), represent culture-bound syndromes and discuss implications for conceptualizing the role genes play in their etiology. The examination is divided into 3 sections: a quantitative meta-analysis of changes in incidence rates since the formal recognition of AN and BN, a qualitative summary of historical evidence of eating disorders before their formal recognition, and an evaluation of the presence of these disorders in non-Western cultures. Findings suggest that BN is a culture-bound syndrome and AN is not. Thus, heritability estimates for BN may show greater variability cross-culturally than heritability estimates for AN, and the genetic bases of these disorders may be associated with differential pathoplasticity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Joint effect of dopaminergic genes on likelihood of smoking following treatment with bupropion SR.

Objective: To determine the relationship between joint variation in 2 dopaminergic genes and the likelihood of nonsmoking following treatment with bupropion sustained release (SR). Design: Three hundred twenty-three participants in a bupropion SR smoking cessation effectiveness trial with 12-month follow-up were genotyped for variants of dopamine receptor gene DRD2 and dopamine transporter SLC6A3. Main Outcome Measures: Self-reported 7-day point prevalence of nonsmoking. Results: Neither genotype alone was associated with 7-day point-prevalent nonsmoking at the 12-month follow-up. However, in the presence of the DRD2 A1 allele, SLC6A3 status was significantly associated with the likelihood of nonsmoking at the 12-month follow-up (individuals with DRD2 A1+ and SLC6A3 9- were more likely to be smoking). In the absence of the DRD2 A1 allele, the association between SLC6A3 status and nonsmoking was nonsignificant. Conclusion: Although these results are suggestive, a more compelling test is needed of the hypothesis that dopaminergic gene interaction underlies, in part, the likelihood of smoking following treatment with bupropion SR. Most likely this will come from larger studies involving prospective randomization to treatment based on genotype. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence suggesting the role of specific genetic factors in cigarette smoking.

Twin studies suggest that propensity to smoke and ability to quit smoking are influenced by genetic factors. As a means of investigating the risk of smoking associated with genetic polymorphisms in the dopamine transporter (SLC6A3) and the D? dopamine receptor (DRD2) genes, a case-control study of 289 smokers and 233 nonsmoking controls and a case series analysis of smokers were conducted. A significant effect for SLC6A3 and a significant gene-gene interaction were found in a logistic regression model, indicating that individuals with SLC6A3-9 genotypes were significantly less likely to be smokers, especially if they also had DRD2-A2 genotypes. Smokers with SLC6A3-9 genotypes were also significantly less likely to have started smoking before 16 years of age and had prior smoking histories indicating a longer period of prior smoking cessation. This study provides preliminary evidence that the SLC6A3 gene may influence smoking initiation and nicotine dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)