The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have ...only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 x 10(-8), experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.
A method for prediction of disease relevant human genes from the phenotypic appearance of a query disease is presented. Diseases of known genetic origin are clustered according to their phenotypic ...similarity. Each cluster entry consists of a disease and its underlying disease gene. Potential disease genes from the human genome are scored by their functional similarity to known disease genes in these clusters, which are phenotypically similar to the query disease.
For assessment of the approach, a leave-one-out cross-validation of 878 diseases from the OMIM database, using 10672 candidate genes from the human genome, is performed. Depending on the applied parameters, in roughly one-third of cases the true solution is contained within the top scoring 3% of predictions and in two-third of cases the true solution is contained within the top scoring 15% of predictions. The prediction results can either be used to identify target genes, when searching for a mutation in monogenic diseases or for selection of loci in genotyping experiments in genetically complex diseases.
Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study ...(GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340 kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P=0.05; odds ratio (OR)=1.24) and German (P=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (P=3 x 10(-6); OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P=0.0001; OR=1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P=1.7 x 10(-5); OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker x marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.
Individuals carrying germline mutations in one of the genes responsible for hereditary nonpolyposis colon cancer (HNPCC) have a lifetime risk of up to 80 % of developing colorectal cancer. As there ...is evidence for a higher incidence of flat adenomatous precursors and because an accelerated adenoma-carcinoma sequence has been postulated for these patients, early detection of these lesions is essential. It was the aim of the present study to assess the detection rate of polypoid lesions by comparing chromocolonoscopy with standard white light colonoscopy and narrow-band imaging (NBI) colonoscopy.
109 patients were included (98 with a functionally relevant mutation in a mismatch repair gene, 11 fulfilling the strict Amsterdam criteria). In 47 patients, standard colonoscopy was followed by chromocolonoscopy with indigo carmine. In 62 patients, NBI was performed first followed by chromocolonoscopy.
A total of 128 hyperplastic and 52 adenomatous lesions were detected. In the first series, 0.5 lesions/patient were identified by standard colonoscopy and 1.5 lesions/patient by chromocolonoscopy ( P < 0.001). In the second series, 0.7 lesions/patient were detected by NBI colonoscopy and 1.8 lesions/patient by chromocolonoscopy ( P = 0.01). At least one adenoma was detected in 15 % of patients by both standard and NBI colonoscopy compared with 28 % of patients by chromocolonoscopy.
According to this study, chromocolonoscopy detects significantly more hyperplastic and, in particular, adenomatous lesions than standard white light colonoscopy or NBI.
A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in ...German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.
Background:In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown.Methods:Mutation and phenotype analysis was used in 80 ...unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS.Results:By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS).Conclusions:Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.
Because in most patients with mental retardation (MR), who constitute 2 to 3% of the population, the etiology remains unknown, we wanted to identify novel chromosomal candidate regions and genes ...associated with the MR phenotype.
We screened for microimbalances in 60 clinically well-characterized patients with unexplained MR mostly combined with congenital anomalies. Genome-wide array-based comparative genomic hybridization was performed on DNA microarrays with an average resolution of <0.5 Mb. We verified every nonpolymorphic array clone outside the diagnostic thresholds by fluorescence in situ hybridization and performed breakpoint analyses on confirmed imbalances.
Six presumably causal microimbalances were detected, five of which have not been reported. Microdeletions were found in five patients with MR and distinctive facial features, who also had neurologic findings (three cases), brain anomalies (two cases), and growth retardation (two cases), in chromosomal bands 6q11.1-q13 (10.8 Mb), Xq21.31-q21.33 (4.0 Mb), 1q24.1-q24.2 (3.8 Mb), 19p13.12 (2.1 Mb), and 4p12-p13 (1.1 Mb). One microduplication was detected in 22q11.2 (2.8 Mb) including the DiGeorge syndrome critical region in a patient with mild MR, microcephaly at birth, and dysmorphisms. Three imbalances were shown to be de novo and two inherited. The Xq21 microdeletion in a boy with borderline intellectual functioning was inherited from a normal mother; the 22q11.2 microduplication was inherited from a normal father and was present in two affected siblings.
We could identify novel microimbalances as the probable cause of mental retardation in 10% of patients with unclear etiology. The gene content of the microimbalances was found to correlate with phenotype severity. Precise breakpoint analyses allowed the identification of deleted genes presumably causing mental retardation.
We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A ...total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.
A Potassium Channel Mutation in Neonatal Human Epilepsy Biervert, Christian; Schroeder, Björn C.; Kubisch, Christian ...
Science (American Association for the Advancement of Science),
01/1998, Letnik:
279, Številka:
5349
Journal Article
Recenzirano
Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene ...(KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.
A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular ...mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, χ2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients.
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