Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

[Obligatory vaccination reporting in Saxony-Anhalt. Possibilities and limitations of establishing a computerized vaccination registry]. / Impfmeldepflicht in Sachsen-Anhalt. Möglichkeiten und Grenzen der Entwicklung eines elektronischen Impfregisters.

Vaccination registries are databases intended to assess and manage complete vaccination data of as many individuals as possible in a population under survey. The task of these registries is to identify low vaccination rates on the individual and population level, to enable systems of reminding individuals, to focus vaccination campaigns and to maximize overall vaccination coverage. Saxony-Anhalt is the only federal state of Germany to have a law that prescribes the reporting of vaccinations. Vaccinations of children up to the age of 7 are reported to the regional public health services. However, as the law provides no regulations as to how the data should be registered and processed, the development of a vaccination registry depends entirely on the initiative and cooperation of the "players in vaccination". The key players in vaccination in Saxony-Anhalt have recently created a Vaccination-Committee, which set out to develop the theoretical standards and a software prototype for the establishment of a computerized vaccination registry. Recent developments in the public health reporting system of Saxony-Anhalt (which strives to modernize its computerized assessment of child and adolescent health) are now opening the possibility to integrate the vaccination registry into the commercially available child health software.

[Meningococcal carriers in high school students and possible risk factors]. / Meningokokken-Trägerstatus von Gymnasiasten und mögliche Risikofaktoren.

From August 2004 to January 2005 a cluster of 7 cases of serogroup B meningococcal disease occurred in the state of Saxony-Anhalt in the town of Sangerhausen and the surrounding area. This led to an investigation of meningococcal carriage in 816 high school students (grades 9 to 13). The students were also asked to fill out a questionnaire regarding possible risk factors for carriage. The goal of the study was the evaluation of a possibly persistently increased risk for further cases in the region. Results of the study were to be used for a comprehensive and targeted education of the public. The percentage of students found harbouring N. meningitidis in the nasopharynx in Sangerhausen (9.0 %) was not elevated compared to that found in the two control regions of Kelbra, County of Sangerhausen (8.2 %) and Jessen, County of Wittenberg (9.9 %). The serogroup B fine type responsible for the cluster (P1.7-2,16:F3-3:PorB3-24) was found only in one student each in Sangerhausen and Kelbra. Thus, there was no evidence of an increased risk for further cases at the time of the study at the end of January, 2005. This may have been due to intensive contact tracing and provision of chemoprophylaxis in Sangerhausen. Visiting a disco or bar and smoking were identified as risk factors for meningococcal carriage. However, these factors were associated with carriage only in boys but not in girls. This may be explained by sex-specific differences in physical interaction with others. Efforts to prevent further cases during clusters of meningococcal disease should consider sex-specific risk behaviour.

Are there gender differences in neuropsychological performance in patients with first-episode schizophrenia?

To investigate gender differences in neuropsychological (NP) functioning in first episode (FE) schizophrenia, consecutively recruited patients with FE schizophrenia (37 males, 29 females) and a subsample of these patients (20 males, 20 females), individually matched for gender, age, and education to healthy controls (20 males, 20 females) were compared on a battery of standardized neuropsychological tests. Women performed better than men in tests of verbal memory and learning, and men performed better than women in spatial organization. However, no differences were present between schizophrenic patients and controls, except that male and female schizophrenic patients showed the most pronounced impairment in visual motor processing, attention and verbal memory and learning. Our data suggest that gender does not appear markedly to modify the cognitive impairment characteristic of schizophrenia. However, they underline the necessity of controlling confounding factors on NP performance such as gender and education.

Genetic relationship between dopamine transporter gene and schizophrenia: linkage and association.

This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.

Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene.

We report two novel polymorphisms and a rare deletion variant in the human dopaine D4 receptor gene. The two polymorphisms are characterized by single base pair substitutions, namely a G-->C transversion changing codon 11 from GGG (encoding Gly) to CGG (encoding Arg) and a C-->T transition in position -11 upstream from the start codon. The Arg11 variant occurs at a frequency of about 1% and the C-->T transition at a frequency of about 7% in German control subjects (n = 148). Allele frequencies observed in patients suffering from schizophrenia (n = 256) and bipolar affective disorder (n = 99) were similar. The deletion variant is characterized by a 21 bp deletion affecting codons 36 to 42 coding for amino acids Ala-Ala-Leu-Val-Gly-Gly-Val located in the first transmembrane domain of the dopamine D4 receptor. The mutation was identified in a single individual suffering from obsessive-compulsive disorder and panic disorder. We were unable to detect the deletion in patients with schizophrenia and bipolar affective disorder, nor in healthy controls.

hSKCa3: no association of the polymorphic CAG repeat with bipolar affective disorder and schizophrenia.

hSKCa3 is a neuronal small conductance calcium-activated potassium channel, which contains a polyglutamine tract, encoded by a polymorphic CAG repeat in the gene. Since an association between longer alleles of this CAG repeat and bipolar disorder or schizophrenia has been reported, we genotyped the polymorphic CAG repeat in 91 German family trios of patients with bipolar disorder I and used the transmission disequilibrium test (TDT) to test for association. Applying a dichotomized model (< or = 19 or > 19 CAG triplets), we found no evidence for an association of longer alleles with bipolar disorder (TDT = 0.75, P = 0.386). Regarding the whole range of alleles, there was no preference in transmitting the larger of the two observed alleles from parents to the affected offspring. In parallel we performed an independent case-control study on German patients with bipolar disorder and schizophrenia. Again we did not detect an overrepresentation of longer CAG repeats in patients. Thus, our data do not support the hypothesis that longer CAG repeats in the hSkCa3 gene contribute to the susceptibility for bipolar disorder and schizophrenia.

[Experiences and difficulties in implementing immunization registries in Saxony-Anhalt]. / Erfahrungen und Schwierigkeiten bei der Implementierung von Impfregistern in Sachsen-Anhalt.

In the German Federal State of Saxony-Anhalt, the Health Department must be notified of vaccines administered to children <7 years of age including their names. The goal of this mandatory notification is to improve and stabilize the age-appropriate vaccination coverage. However, difficulties have been encountered in implementing mandatory notification. Therefore, the Health Departments of Magdeburg and Halle have launched a model project focusing on analysing and eliminating these problems. Mandatory notification requires parents' approval, endorsement of vaccantors, and availability of human and technicely resources in the Health Department. An enquiry among paediatricians and family doctors in private practice revealed widespread reservations about mandatory notification because of privacy issues related to data and legal protection. Furthermore, family doctors believed that parents disapproved of notification by name. However, a survey among young mothers revealed this not to be the case. Winning young mothers' approval depends largely on the positive attitude of the vaccinators. To implement the mandatory notification of vaccinations to the Health Department, it is necessary to dispel physicians' concerns and to inform young parents about the practical benefits. However, this places high demands on the Health Departments for maintaining immunization registries, communicating with physicians and notifying parents when immunisations are due or late.

Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis.

Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.

A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6.

Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.

The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder.

In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.

Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis.

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/parents trios.

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings.

The serotonergic (5-HT) system has been implicated in the etiopathogenesis of psychoses. Since the 5-HT transporter plays an important role in regulation of 5-HT transmission, its gene can be considered as a candidate for vulnerability to psychiatric disorders. Two polymorphic sites of the 5-HT transporter gene-5-HTTLPR, a VNTR in the 5' regulatory region, and a VNTR in the second intron-were studied in a sample of 61 families with schizophrenia for transmission disequilibrium. Each family contained at least two siblings affected with schizophrenia or schizoaffective disorder (mainly schizophrenic). One hundred and thirty-nine affected offspring with parental information for genotyping, were available for analysis. No preferential transmission of either short or long alleles of the promoter polymorphism was observed. However, a transmission distortion was detected for alleles of the intronic VNTR polymorphism (chi2TDT max =14.33; P = 0.0002; corrected P value = 0.0003) resulting in more frequent than expected transmission of the 12 repeat allele. This finding adds additional evidence to the idea that the serotonergic system may be involved in development of psychoses. Molecular Psychiatry (2000) 5, 91-95.