Copper genes are not implicated in the pathogenesis of focal dystonia.
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Adenosine Triphosphatases↗
Biomedical subjects
D B Wildenauer
Publications and source records attributed to D B Wildenauer.
Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.
A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.
Case-Control Studies↗
Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD).
Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.
Adenosine Triphosphatases↗
Transmission/disequilibrium tests using multiple tightly linked markers.
Transmission/disequilibrium tests have attracted much attention in genetic studies of complex traits because (a) their power to detect genes having small to moderate effects may be greater than that of other linkage methods and (b) they are robust against population stratification. Highly polymorphic markers have become available throughout the human genome, and many such markers can be studied within short physical distances. Studies using multiple tightly linked markers are more informative than those using single markers. However, such information has not been fully utilized by existing statistical methods, resulting in possibly substantial loss of information in the identification of genes underlying complex traits. In this article, we propose novel statistical methods to analyze multiple tightly linked markers. Simulation studies comparing our methods versus existing methods suggest that our methods are more powerful. Finally, we apply the proposed methods to study genetic linkage between the dopamine D2 receptor locus and alcoholism.
Alcoholism↗
Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III.
Schizophrenia candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p, and 13q were investigated for genetic linkage with mapped markers with an average spacing of 5.64 cM. We studied 734 informative multiplex pedigrees (824 independent affected sibling pairs [ASPs], or 1,003 ASPs when all possible pairs are counted), which were collected in eight centers. Cases with diagnoses of schizophrenia or schizoaffective disorder (DSM-IIIR criteria) were considered affected (n=1,937). Data were analyzed with multipoint methods, including nonparametric linkage (NPL), ASP analysis using the possible-triangle method, and logistic-regression analysis of identity-by-descent (IBD) sharing in ASPs with sample as a covariate, in a test for intersample heterogeneity and for linkage with allowance for intersample heterogeneity. The data most supportive for linkage to schizophrenia were from chromosome 6q; logistic-regression analysis of linkage allowing for intersample heterogeneity produced an empirical P value <.0002 with, or P=.0004 without, inclusion of the sample that produced the first positive report in this region; the maximum NPL score in this region was 2.47 (P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10 (empirical P=.0036), and there was significant evidence for intersample heterogeneity (empirical P=.0038). More-modest support for linkage was observed for chromosome 10p, with logistic-regression analysis of linkage producing an empirical P=. 045 and with significant evidence for intersample heterogeneity (empirical P=.0096).
Chromosome Mapping↗
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.
Brain Chemistry↗
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.
Chromosome Mapping↗
Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence.
OBJECTIVE: An association between the 5-HTTLPR short variant polymorphism in the promoter region of the serotonin transporter gene and risk for alcohol dependence has been reported from case-control studies that are, however, prone to chance findings related to artifacts of population structure. The authors sought additional evidence for this association from a family-based study. METHOD: Ninety-two alcohol-dependent probands and their parents were tested for nonrandom transmission of alleles from heterozygous parents to affected probands. RESULTS: Preferential transmission of the short allele was found (65 of 102 transmissions from heterozygous parents). CONCLUSIONS: The results suggest allelic association between a variant in the promoter region of the serotonin transporter gene and the risk for alcohol dependence. However, it remains to be seen whether the functional properties of this variant are directly responsible for the increased risk to alcohol dependence.
Adult↗
No evidence for segregation distortion in females in a sample of 72 families with schizophrenia with potential linkage to chromosome 10p14-p11.
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Chromosome Segregation↗
Do schizophrenia and affective disorder share susceptibility genes?
Schizophrenia and affective disorders are relatively common neuropsychiatric diseases with a complex genetic etiology. A multigenic inheritance with variable influence of unknown environmental factors may be involved. Family studies have demonstrated the existence of both phenotypes in the same kindreds, and in certain cases, a transition from one phenotype to another occurs. In addition, intermediate phenotypes such as schizoaffective disorders are found in families with schizophrenia and affective illness. Recent genome and chromosomal scans appear to support these epidemiologic data, since susceptibility regions for both schizophrenia and affective disorders have been found to overlap, on chromosomes 10p13-p12, 13q32, 18p and 22q11-q13. These studies were performed in independently ascertained family samples with index patients afflicted either with schizophrenia or bipolar disorder. Taken together, these findings imply shared loci for schizophrenia and affective disorders among those required for the full expression of the phenotype. Identification and molecular characterization of the genetic components conferring risk to both disorders would impact positively on diagnosis, prevention, and treatment.
Bipolar Disorder↗
Chromosomes 8 and 10 workshop.
The chromosomes 8 and 10 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th-10th, 1998 in Bonn, Germany. Aim of the workshop was to discuss and summarize reports on potential susceptibility genes for psychiatric disorders. Linkage-findings on chromosome 8 concentrate on 8p22-p21 and include mainly schizophrenic disorders. Two areas on chromosome 10 were reported to contain potential susceptibility genes for schizophrenic as well as for affective disorders. The strongest findings were reported for 10p14-p11, while other groups communicated also linkage data for the telomeric part of the long arm to the workshop.
Bipolar Disorder↗
Chromosome 22 workshop report.
The chromosome 22 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th-10th, 1998 in Bonn, Germany. Aim of the workshop was to summarize the findings in psychiatric genetics on chromosome 22. Four reports concerning a susceptibility locus for schizophrenia and one report on bipolar disorder were given. A potential locus for nocturnal enuresis has been suggested to reside on chromosome 22.
Chromosome Mapping↗
DAT1 gene polymorphism in alcoholism: a family-based association study.
BACKGROUND: The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics. METHODS: To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents. RESULTS: By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms. CONCLUSIONS: Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.
Alcoholism↗
Family and genetic studies on the relationship of schizophrenia to affective disorders.
Schizophrenia is a genetically influenced disease with a broad and heterogeneous phenotype transmitted in families. Of particular interest is the familial-genetic relationship between schizophrenia and affective disorders. Taking advantage of refined epidemiological methods, the dichotomy between both groups of disorders is not less consistently found than expected. Recently, linkage studies identified multiple candidate regions for susceptibility genes for each of both disorders. Several of these candidate regions for schizophrenia are overlapping with candidate regions for bipolar disorder. Thus, the hypothesis of an etiological dichotomy of schizophrenia and affective disorders faces a new challenge.
Chromosome Aberrations↗
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.
Female↗
Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis.
Recent reports on potential linkage by Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557], and by Straub et al. [1997: Am J Med Genet 74:558], prompted us to study chromosome 10 in a sample of 72 families containing 2 or more affected sibs with schizophrenia for additional evidence of linkage. We obtained highest allele sharing for the two markers D10S582 (61.5% allele sharing, chi2 = 7.6, P = 0.0058) and D10S1423 (59% allele sharing, chi2 = 4.76, P = 0.029). D10S1423 is one of the markers with the highest lod scores in the study of Faraone and the NIMH Genetics Initiative-Millennium Schizophrenia Consortium [1997: Am J Med Genet 74:557]. GENEHUNTER analysis revealed a nonparametric lod score (NPL) of 3.2 (P = 0.0007) for the marker D10S1714, which lies in the same region. Multipoint affected sib-pair lod score analysis (identity by descent) calculated by ASPEX revealed a lod score of 1.72 for all possible sib-pair combinations (107) and of 2.13, when only independent sib-pairs (87) were counted. Our study provides further evidence for a potential susceptibility locus for schizophrenia on chromosome 10p.
Alleles↗
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.
Chromosomes, Human, Pair 18↗