H.N. Aschauer

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene

BACKGROUND An association between schizophrenia and the T102C polymorphism of the gene for 5-hydroxytryptamine type 2a (5-HT2a) receptor has been reported; the proportion of allele 2 of this polymorphism is higher than expected among schizophrenic patients. We looked for an association between schizophrenia and this variant of the 5-HT2a-receptor gene in a large multicentre study. METHODS Seven countries recruited 1210 participants: 571 white schizophrenic patients and 639 ethnically matched controls. All patients had a diagnosis of schizophrenia or schizoaffective disorder. High-molecular-weight DNA was isolated from lymphocytes. PCR amplification and restriction enzyme digestion was used to examine sequence variation of the 5-HT2a-receptor gene. Genotypes 1/1, 1/2, and 2/2 were assigned. Woolfs method was used to look for an association between schizophrenia and allele 2 and the 2/2 genotype. FINDINGS We found a significant overall association between schizophrenia and allele 2 with an odds ratio of 1.3 (95% Cl 1.1-1.53, p = 0.003). No evidence for heterogeneity was observed between samples. We found a highly significant excess of the 1-2/2-2 genotypes in schizophrenia (p = 0.008) with a relative risk of 1.7 (1.22-2.36) and an attributable fraction of 0.35. INTERPRETATION Our findings suggest that the gene for 5-HT2a-receptor, or a locus in linkage disequilibrium with it, confers susceptibility to schizophrenia. Allele 2 is common in the population and it is, therefore, likely that this variant, or a nearby polymorphism, may affect a significant proportion of schizophrenic patients.

Pharmacogenetics of Tardive Dyskinesia: Combined Analysis of 780 Patients Supports Association with Dopamine D3 Receptor Gene Ser9Gly Polymorphism

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x2=4.46, df 1, p = .04) and with DRD3 genotype (x2=6.62, df 2, p = .04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x2=5.02, df 1, p = .02 for gly allele carrier status; x2 = 7.51, df 2, p = .002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p = .006) or ser-ser homozygotes (p < .0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04–1.70, p = .02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08–1.68, p < .0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia

We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, BalI polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07–1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35–5.86). Although no significant allelic association was observed, a significant association was detected with the 1–1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13–4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09–1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the BalI polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.

Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia.

In the present study, the occurrence of tardive dyskinesia (TD) in chronic schizophrenia patients was investigated in relation to pharmacogenetic polymorphisms. It is known that the metabolism of important neuroleptic drugs is influenced by polymorphisms of the CYP2D6 gene, which encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Forty-five patients meeting the DSM IV criteria for schizophrenia, chronic course, were recruited. The patients were examined for the mutations CYP2D6*3, CYP2D6*4 and CYP2D6*5. The CYP2D6 genotype distribution in the patient group did not differ from that in healthy Caucasian populations. Tardive dyskinesia was found in 26 patients (57.8%). When comparing patients without CYP2D6 mutations with patients heterozygous for one mutation, we found a higher incidence of TD in the latter (81.3% vs. 46.4%, p = 0.031, multiple regression analysis), which demonstrates a significant influence of the CYP2D6 genotype of the manifestation of TD. As slight differences in the metabolism of drugs in patients heterozygous for CYP2D6 mutations and patients without such mutations are known, we conclude that heterozygous carriers of 2D6 mutated alleles may show an increased susceptibility to developing TD.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism

BACKGROUND A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients

Abstract The dopamine D3 receptor (DRD3) appears to play an important role in the mediation of antipsychotic drug action. Genetic association of treatment response to the atypical antipsychotic drug clozapine with the DRD3 polymorphism Ser9Gly was investigated in a sample of 32 schizophrenic patients. We found association of treatment response with allele Gly-9 ( P =0.0058) and with genotypes consisting of Gly-9 ( P =0.033) by this pharmacogenetic approach. A combined analysis with two previous studies (Shaikh et al., Hum. Genet. 97 (1996) 714–719; Malhotra et al., Mol. Psychiatry 3 (1998) 72–75) further substantiates these results ( P =0.0041).

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fishers exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.

Genome scan for susceptibility loci for schizophrenia and bipolar disorder

BACKGROUND Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders. METHODS A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia and three bipolar disorder Austrian families. Linkage analyses was used to compute the usual parametric logarithm of the likelihood of linkage (LOD) scores and nonparametric linkage analysis (NPL scores Z(all)) was used to assess the pattern of allele sharing at each marker locus relative to the presence of the disease (GENEHUNTER). Affected status was defined as severe affective disorder or schizophrenia. RESULTS Across the genome, p values associated with NPL scores resulted in evidence (i.e., p <.0007) for linkage at marker D3S1265 on chromosome 3q (NPL score Z (all) = 3.74, p =.0003). Two other markers (on 3q and 6q) showed p values of <.01. CONCLUSIONS We detected a potential susceptibility locus for bipolar disorder and schizophrenia on chromosome 3q, which has not been reported previously. The possibility of a false positive result has to be taken into account. Our data suggest shared loci for schizophrenia and bipolar affective disorders and are consistent with the continuum model of psychosis.