We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney ...disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.
At present, the cost of genotyping single nucleotide polymorphisms (SNPs) in large numbers of subjects poses a formidable problem for molecular genetic approaches to complex diseases. We have tested ...the possibility of using primer extension and denaturing high performance liquid chromatography to estimate allele frequencies of SNPs in pooled DNA samples. Our data show that this method should allow the accurate estimation of absolute allele frequencies in pooled samples of DNA and also of the difference in allele frequency between different pooled DNA samples. This technique therefore offers an efficient and cheap method for genotyping SNPs in large case-control and family-based association samples.
By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants ...from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.
A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis ...and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.
Synthetic hydrotalcite-like samples with composition M1 − x2+Alx3+(OH)2(CO3)x/2 ·nH2O, where M = Mg, Ni, x = 0.25 and 0.33, n = 2x and 1.5x, are studied by XRD, DTA, TG and IR spectroscopy after ...heating in the temperature interval 120–260 °C and rehydration in air and water. Structural models of the two metaphases obtained are proposed. Metahydrotalcite-D (HT-D) is formed at 140–180 °C by the reversible dehydration of the interlayer. Metahydrotacite-B (HT-B) is formed at temperatures 240–260 °C as a result of the dehydroxilation of a part of OH groups of the brucite-like layer and inclusion of two oxygenes from the CO3-group in the same layer. The HT-B has a specific crystal structure. Rehydration does not restore the initial structural state but leads to the formation of a phase (HT-B-r) characterized with increased thickness of the interlayer, high content of water and a low temperature of dehydration. The properties of HT-B depend on the ratio M2+: Al of the initial sample. The substitution Mg ↔ Ni does not influence the properties of the metaphases in the low temperature region.
Interestingly, in three of the four families in which Goldschmidt's highly myopic probands had an affected sib, one or more of the parents was also affected. ...in the nine families that had at least ...one affected parent, 50% of sibs were affected. ...it was noted that the frequency distribution of myopia in Goldschmidt's unselected child population group conformed well to a biphasic distribution, consistent with the occurrence of two aetiologically distinct, major forms of myopia.
Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations ...(CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.
Velo-cardio-facial syndrome (VCFS) is associated with interstitial deletions of chromosome 22q11. About 30% of patients with VCFS have psychosis, and the rate of these deletions in schizophrenia has ...been reported to be about 1%. Even higher rates of VCFS deletions have been reported for childhood-onset schizophrenia.
To test the hypothesis that there is an increased rate of VCFS among patients with early-onset psychosis (age at onset <18 years). We screened 192 early-onset patients and 329 patients with adult-onset schizophrenia.
We genotyped the patients and 444 healthy controls for hemizygosity of five microsatellite markers and one single nucleotide polymorphism that map to the 22q11-deleted region.
One patient had a VCFS deletion, confirmed with semi-quantitative polymerase chain reaction. None of the controls showed a pattern of genotypes consistent with hemizygosity.
VCFS may be less frequent among patients with psychosis than previously suggested; this rate is not increased among early-onset patients.
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