Judith Körner

Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: Identification of two naturally occurring receptor variants and association analysis in schizophrenia

A statistically significant association between a silent mutation (102T/C) in the serotonin-2A (5-HT2A) receptor gene and schizophrenia has recently been reported in a sample of Japanese patients and healthy controls. This finding suggests that genetic predisposition to schizophrenia may be affected by a functional 5-HT2A receptor variant that is in linkage disequilibrium with 102T/C. In the present study, we have sought to identify genetic variation in the 5-HT2A receptor gene by screening genomic DNA samples from 91 unrelated subjects comprising 45 patients with schizophrenia and 46 healthy controls by using single-strand conformation analysis. We have identified four nucleotide sequence variants. Two sequence changes would result in protein alterations: a substitution of threonine by asparagine at position 25 (Thr25Asn), and a substitution of histidine by tyrosine at position 452 (His452Tyr). In order to test for a possible contribution to the development of schizophrenia, we have determined allele frequencies in extended samples of unrelated patients and healthy controls. The two amino acid substitutions are found with similar frequencies in patients and controls, indicating that the presence of these variants is not causally related to the development of schizophrenia. However, the reported association of the non-coding polymorphism 102T/C with the disease has also been detected in our sample (P = 0.041, odds ratio = 1.28, 95% confidence interval 1.012–1.623).

A serine to glycine substitution at position 9 in the extracellular N-terminal part of the dopamine D3 receptor protein: No role in the genetic predisposition to bipolar affective disorder☆

Association studies offer a promising tool to investigate the potential role of DNA sequence variation affecting the expression or sequence of proteins in susceptibility to common diseases. We determined the frequency of a DNA polymorphism resulting in a glycine to serine substitution at position 9 in the extracellular N-terminal part of the dopamine D3 receptor protein in a sample of 83 patients suffering from bipolar affective disorder and 100 control subjects. No significant differences between the groups were found. Thus, this substitution, which is the first sequence variation identified in the dopamine D3 receptor gene altering the amino acid sequence of the protein, can be regarded as a protein variant with no major effect on the susceptibility to bipolar affective disorder.

Lack of association between schizophrenia and alleles of the dopamine D1, D2, D3 and D4 receptor loci1

The dopamine system is a preferred object of biological research in schizophrenia. The evolving delineation of distinct multiple human dopamine receptors and the increasing availability of polymorphic DN A probes from the receptor loci allows to test for the involvement of the dopamine receptor genes in the etiology of the disease. Sixty schizophrenic patients and 60 control subjects were examined for association of genetic polymorphisms at the Dl, D2, D3 and D4 dopamine receptor gene loci. No significant differences of genotype or allele frequencies could be found between patients and controls. Our findings do not support the hypothesis that a single mutant form of one of the dopamine receptor genes under study is commonly involved in the etiology of schizophrenia. In addition, no significant differences in the prevalence of a glycine to serine substitution at position 9 in the extracellular N-terminal part of the dopamine D3 receptor gene were observed between schizophrenics and controls. Therefore, this substitution can be regarded as a protein variation with no major effect on susceptibility to schizophrenia.

Association and haplotype analysis at the tyrosine hydroxylase locus in a combined German-British sample of manic depressive patients and controls.

Tyrosine hydroxylase (TH) is the key enzyme in the synthesis of catecholamines and may therefore be of aetiological relevance in the development of psychiatric illness. Hipolar affective disorder association studies, with restriction fragment length polymorphisms located in flanking regions of the TH gene, have shown conflicting results. Alleles of a tetranucleotide repeat polymorphism (TH4) located in intron 1 of the gene were tested for association with bipolar affective disorder in a combined German and British sample of 183 bipolar patients and 209 healthy control probands. No differences in TH4 allele frequencies were found in the two groups. A subset of patients and controls was typed with the flanking markers Ty7/Bg/II and pJ4.7/TaqI and frequencies of two-locus haplotypes were estimated. Linkage disequilibrium was found between TH4-Ty7 and TH4-pJ4.7. Haplotype frequencies did not differ between patients and controls.

An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia.

Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin‐3 (NT‐3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT‐3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy‐Weinberg equilibrium and, in a test of all alleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P= 0.029).

Dopamine D3 receptor Gly9/Ser9 polymorphism and schizophrenia: no increased frequency of homozygosity in German familial cases

Disturbances in the dopaminergic transmission have been implicated in the etiology of schizophrenia. Recently, an association of schizophrenia with increased homozygosity of a Gly9/Ser9 polymorphism in the dopamine D3 receptor gene (DRD3) has been reported (Crocq et al., 1992; Mant et al., 1994). This finding reflected a departure from the Hardy-Weinberg equilibrium in the genotype distribution observed in schizophrenic patients. The effect was found to be at its strongest in patients with a high familial loading. In the present study, we tried to replicate this finding in a sample of 146 German patients with a DSM-III-R diagnosis of schizophrenia. All patients had a positive family history of major psychiatric disorder including 70 patients with a family history of schizophrenia. Given our sample size, we have a power of 99.8% to detect 2. deviation from the Hardy-Weinberg equilibrium of the reported magnitude. However, we found no evidence of an excess of homozygosity in our schizophrenic patients. This seems to indicate that homozygosity for the Gly9/Ser9 polymorphism at the DRD3 locus is unlikely to confer susceptibility to schizophrenia in the German population. This held true whether the psychiatric diagnoses in the affected relatives of the patient samples was established by the family history or family interview method.

Apolipoprotein E genotype distribution in schizophrenia

We examined the hypothesis that apolipoprotein E (apoE) isoforms - besides their well-established role in the aetiology of early and late onset Alzheimers disease (AD) - may be involved in the development of schizophrenia. We determined apoE genotypes in 98 schizophrenic patients and 98 sex and age matched controls. No significant difference in apoE allele frequencies were observed between schizophrenic patients, subpopulations of schizophrenics, or controls. There was also no difference in the mean age at onset depending on the number of apoE ϵ4 alleles found in the patients. Our data do not support an association between AD and schizophrenia based on apoE acting as a common denominator in the pathogenesis of both diseases.

An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia

The cytochrome P450 mono-oxygenases are a group of enzymes that metabolize a variety of exogenous and endogenous compounds, some of which are potentially toxic. Individual variations in the metabolism of potential toxins could influence susceptibility to disorders having genetic and environmental components, such as schizophrenia. The frequency of two common mutant alleles of the gene for the cytochrome P450 enzyme debrisoquine-4-hydroxylase (CYP2D6) was determined in 264 Caucasian schizophrenic patients and 217 controls, using the polymerase chain reaction and restriction enzyme digestions. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and the frequency of each mutant allele (CYP2D6A and CYP2D6B) did not differ between patients and controls.

Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia

Using single strand conformational analysis we screened the complete coding sequence of the serotonin 1F (5-HT1F) receptor gene for the presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic patients, 46 bipolar patients, as well as 46 healthy controls. We detected only three rare sequence variants which are characterized by single base pair substitutions, namely a silent T-->A transversion in the third position of codon 261 (encoding isoleucine), a silent C-->T transition in the third position of codon 176 (encoding histidine), and an C-->T transition in position -78 upstream from the start codon. The lack of significant mutations in patients suffering from schizophrenia and bipolar affective disorder indicates that the 5-HT1F receptor is not commonly involved in the etiology of these diseases.

Hailey-Hailey disease and bipolar affective disorder in three members of the same family

Zusammenfassung. Wir berichten über eine Kosegregation von Morbus Hailey-Hailey (MHH) und bipolarer affektiver Erkrankung bei drei Mitgliedern einer Familie. Mit dem Fortschritt molekularbiologischer Techniken ist die Genlokalisation bei Erkrankungen mit einfachem Vererbungsmuster, wie dem autosomal-dominant vererbten MHH, eine Frage der Zeit. Die chromosomale Region des MHH-Gens wird dann auch Kandidatenregion für Kopplungsanalysen bei affektiven Erkrankungen sein.Summary. We report on three family members suffering from both autosomal dominant Hailey-Hailey disease and bipolar affective disorder. As molecular biology techniques have made the localization of genes causing simple Mendelian traits possible as a routine task, the gene for Hailey-Hailey disease will presumably be localized in the foreseeable future. The Hailey-Hailey gene and its chromosomal surrounding will then be a region of interest for linkage studies in bipolar affective disorder.