How to manage the first episode of schizophrenia. Innovations in service provision need evidence, not opinion.
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Cognitive Behavioral Therapy↗
Biomedical subjects
D Curtis
Publications and source records attributed to D Curtis.
Coeliac disease: follow-up linkage study provides further support for existence of a susceptibility locus on chromosome 11p11.
Susceptibility to coeliac disease has a strong genetic component. The HLA associations have been well described but it is clear that other genes outside this region must also be involved in disease development. Two previous genome-wide linkage studies using the affected sib pair method produced conflicting results. Our own family based linkage study of 16 highly informative pedigrees identified 17 possibly linked regions, each of which produced a result significant at p & 0.05 or less. We have now investigated these 17 regions in a larger set of pedigrees using more finely spaced markers. Fifty multiply affected families were studied, comprising the 16 pedigrees from the original genome screen plus 34 new highly informative pedigrees. A total of 128 microsatellite markers were genotyped with an average spacing between markers of 5 cM. Two-point and three-point linkage analysis using classical and model free methods identified five potential susceptibility loci with heterogeneity lod scores > 2.0, at 6p12, 11p11, 17q12, 18q23 and 22q13.3. The most significant was a heterogeneity lod of 2.6 at D11S914 on chromosome 11p11. This marker maps to a position implicated in one of the two previous genome scans and taken together these results provide strong support for the existence of a susceptibility locus in this region.
Celiac Disease↗
A novel method of two-locus linkage analysis applied to a genome scan for late onset Alzheimer's disease.
A number of methods have previously been described which carry out linkage analysis considering information for two or more loci simultaneously. Apart from some ad hoc methods such as analysing subsamples, these methods use information regarding linkage at all loci under consideration. However, if the actual genotype-specific effects are known for some loci then it would be preferable to consider the genotypes of these loci directly, rather than the amount of allele-sharing they demonstrate. Here we present an extension to our likelihood-based method of model-free linkage analysis as implemented in the MFLINK program. This allows the incorporation of liability classes. The genotypes of a locus known to affect risk can be used to assign subjects to liability classes prior to carrying out linkage tests at other loci. An example application is presented for genome scan data on Alzheimer's disease with analysis conditional on Apoliprotein E (APOE) genotypes. The results provide support for the existence of additional susceptibility loci linked to D10S1211 and to D12S358.
Alzheimer Disease↗
Genetic association studies of schizophrenia using the 8p21-22 genes: prepronociceptin (PNOC), neuronal nicotinic cholinergic receptor alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1).
Schizophrenia is a common, genetically heterogeneous disorder with a lifetime prevalence of approximately 1% in the general population. Linkage studies of affected families have now strongly implicated a susceptibility locus on chromosome 8p21-22. Tests of allelic association with markers on 8p21-22 should be able to localise any quantitative trait nucleotides (QTN's) or susceptibility mutations to within a few hundred kilobases. Three brain expressed candidate susceptibility genes, prepronociceptin (PNOC), neuronal cholinergic receptor, nicotinic, alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1) have been mapped to chromosome 8p21-22. A case-control, allelic association study was performed using a novel highly polymorphic dinucleotide repeat, D8S2611 near the PNOC gene, two previously characterised dinucleotide repeats, D8S131 and D8S131P at the CHRNA2 locus and an RFLP at the 3'UTR of the arylamine N-acetyltransferase 1 (NAT1) gene. No differences were found in allele frequencies between the patient and control groups. DNA variations or mutations at or near the three genes under study are unlikely to increase susceptibility to schizophrenia in our population sample.
3' Untranslated Regions↗
Use of an artificial neural network to detect association between a disease and multiple marker genotypes.
Single nucleotide polymorphisms (SNPs) are very common throughout the genome and hence are potentially valuable for mapping disease susceptibility loci by detecting association between SNP markers and disease. However as SNPs are biallelic they may have relatively little power in association studies compared with the information that would be obtainable if marker haplotypes were available and could be used efficiently. Modelling the evolutionary events leading to linkage disequilibrium is very complex and many methods that seek to use information from multiple markers simultaneously need to make simplifying assumptions and may only be applicable when marker haplotypes, rather than genotypes, are available for analysis. We explore the properties of a simple application of a standard artificial neural network to this problem. The pattern-recognition properties of the network are used in the hope that marker haplotypes implicit in the genotypes will differ between cases and controls in a way which will lead to the network being able to classify the subjects correctly, according to their marker genotype. This method makes no assumptions at all regarding population history or the marker map, and can be applied to genotypes, as would be available from a simple case-control sample, without any need to determine haplotypes. Through application to data simulated under a very wide range of assumptions we show that such an analysis produces a useful augmentation in power above that which would be achieved by testing each marker individually, in particular when more than one mutation has occurred in a disease gene at different points in evolution. The application of neural networks to such problems shows considerable promise and further work could usefully be directed towards optimising the design and implementation of such networks.
Alleles↗
Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23.
We have performed genetic linkage analysis in 13 large multiply affected families, to test the hypothesis that there is extensive heterogeneity of linkage for genetic subtypes of schizophrenia. Our strategy consisted of selecting 13 kindreds containing multiple affected cases in three or more generations, an absence of bipolar affective disorder, and a single progenitor source of schizophrenia with unilineal transmission into the branch of the kindred sampled. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10-cM intervals across the whole genome. We observed LOD scores >3.0 at five distinct loci, either in the sample as a whole or within single families, strongly suggesting etiological heterogeneity. Heterogeneity LOD scores >3.0 in the sample as a whole were found at 1q33.2 (LOD score 3.2; P=.0003), 5q33.2 (LOD score 3.6; P=.0001), 8p22.1-22 (LOD score 3.6; P=.0001), and 11q21 (LOD score 3.1; P=.0004). LOD scores >3.0 within single pedigrees were found at 4q13-31 (LOD score 3.2; P=.0003) and at 11q23.3-24 (LOD score 3.2; P=.0003). A LOD score of 2.9 was also found at 20q12.1-11.23 within in a single family. The fact that other studies have also detected LOD scores >3.0 at 1q33.2, 5q33.2, 8p21-22 and 11q21 suggests that these regions do indeed harbor schizophrenia-susceptibility loci. We believe that the weight of evidence for linkage to the chromosome 1q22, 5q33.2, and 8p21-22 loci is now sufficient to justify intensive investigation of these regions by methods based on linkage disequilibrium. Such studies will soon allow the identification of mutations having a direct effect on susceptibility to schizophrenia.
Chromosome Aberrations↗
Politics and humanitarian aid.
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Altruism↗
The effect of child characteristics on teachers' acceptability of classroom-based behavioral strategies and psychostimulant medication for the treatment of ADHD.
Studied the effect of student characteristics on teachers' ratings of treatment acceptability for attention deficit hyperactivity disorder (ADHD). Participants (N = 159) included experienced elementary school teachers who read 1 of 6 vignettes describing a child with symptoms representative of ADHD. Vignettes varied by sex and symptom-subtype classification. However, the number and specific type of symptoms described in the vignettes were consistent across all conditions. Next, teachers read a description of a daily report card (DRC), response cost technique, classroom lottery, and medication and rated their levels of agreement to the items of the Behavioral Intervention Rating Scale (BIRS). Teachers preferred the DRC to all other forms of treatment. However, there was a significant interaction between the type of treatment and sex of the student on the 3 factors (Treatment Acceptability, Treatment Effectiveness, and Timeliness) of the BIRS.
Adolescent↗
Multimarkerhaplotypes within the serotonin transporter gene suggest evidence of an association with bipolar disorder.
Previously we obtained modest linkage evidence implicating 17q11. 1-12 in bipolar disorder. A modified genome screen, based on gene-rich regions, on a collection of Irish sib-pair nuclear families revealed excess allele sharing at markers flanking the gene encoding the serotonin transporter (5-HTT; hSERT). Here we describe a study designed to combine the advantages of family-based association studies with the consideration of multiple polymorphic markers within a candidate gene. Ninety-two Irish families, with a total of 106 proband-parent trios, have been genotyped for 3 previously known polymorphisms within hSERT (5-HTTLPR, intron 2 VNTR, and 3' UTR G/T). Data from two and three polymorphic marker haplotypes revealed a number of marker combinations that showed evidence supportive of association; the most significant being for polymorphisms 5-HTTLPR and 3' UTR G/T (global chi(2), 12.91, df 3, P = 0.005). In addition, modest evidence of association also was observed for 5-HTTLPR alone. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:845-849, 2000.
Alleles↗
C282Y mutation and type 2 diabetes. Study was much too small for inferences to be drawn.
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Diabetes Mellitus, Type 2↗
Power comparison of parametric and nonparametric linkage tests in small pedigrees.
When the mode of inheritance of a disease is unknown, the LOD-score method of linkage analysis must take into account uncertainties in model parameters. We have previously proposed a parametric linkage test called "MFLOD," which does not require specification of disease model parameters. In the present study, we introduce two new model-free parametric linkage tests, known as "MLOD" and "MALOD." These tests are defined, respectively, as the LOD score and the admixture LOD score, maximized (subject to the same constraints as MFLOD) over disease-model parameters. We compared the power of these three parametric linkage tests and that of two nonparametric linkage tests, NPLall and NPLpairs, which are implemented in GENEHUNTER. With the use of small pedigrees and a fully informative marker, we found the powers of MLOD, NPLall, and NPLpairs to be almost equivalent to each other and not far below that of a LOD-score analysis performed under the assumption the correct genetic parameters. Thus, linkage analysis is not much hindered by uncertain mode of inheritance. The results also suggest that both parametric and nonparametric methods are suitable for linkage analysis of complex disorders in small pedigrees. However, whether these results apply to large pedigrees remains to be answered.
Chromosome Mapping↗
The effect of marker characteristics on the power to detect linkage disequilibrium due to single or multiple ancestral mutations.
An important design issue in allelic association studies for mapping disease genes is the choice of markers. We have used a simple model of a founder population, similar to those of Ott & Rabinowitz (1997) and Chapman & Wijsman (1998), to explore the effect of the number of alleles at a marker polymorphism on the power to detect linkage disequilibrium due to single or multiple ancestral disease mutations. We show that the optimal number of alleles is more than 2 even in the case of a single ancestral disease mutation, and much higher still if multiple ancestral mutations are present. In large samples, much power is lost by using too few alleles, but relatively little power is lost by using too many alleles. These results confirm the desirability of using highly polymorphic markers or multi-locus haplotypes for association analysis. They also show that multiple ancestral disease mutations do not necessarily preclude linkage disequilibrium mapping, if highly polymorphic markers or multi-locus haplotypes are used.
Chi-Square Distribution↗
Amitriptyline treatment of chronic pain in patients with temporomandibular disorders.
Randomized clinical trials of amitriptyline will require data from pilot studies to be used for sample size estimates, but such data are lacking. This study investigated the 6-week and 1-year effectiveness of low dose amitriptyline (10-30 mg) for the treatment of patients with chronic temporomandibular disorder (TMD) pain. Based on clinical examination, patients were divided into two groups: myofascial and mixed (myofascial and temporomandibular joint disorders). Baseline pain was assessed by a Visual Analogue Scale (VAS) for pain intensity and by the McGill Pain Questionnaire (MPQ). Depression was assessed by the Beck Depression Inventory (BDI) short form. Patient assessment of global treatment effectiveness was obtained after 6 weeks and 1 year of treatment by using a five-point ordinal scale: (1) worse, (2) unchanged, (3) minimally improved, (4) moderately improved, (5) markedly improved. The results showed a significant reduction for all pain scores after 6 weeks and 1 year post-treatment. The depression scores changed in depressed but not in non-depressed patients. Global treatment effectiveness showed significant improvement 6 weeks and 1 year post-treatment. However, pain and global treatment effectiveness were less improved at 1 year than at 6 weeks.
Adult↗
A genome-wide family-based linkage study of coeliac disease.
The susceptibility to develop coeliac disease (CD) has a strong genetic component, which is not entirely explained by HLA associations. Two previous genome wide linkage studies have been performed to identify additional loci outside this region. These studies both used a sib-pair design and produced conflicting results. Our aim is to identify non-MHC genetic loci contributing to coeliac disease using a family based linkage study. We performed a genome wide search in 16 highly informative multiply affected pedigrees using 400 microsatellite markers with an average spacing of 10 cM. Linkage analysis was performed using lod score and model free methods. We identified two new potential susceptibility loci with lod scores of 1.9, at 10q23.1, and 16q23.3. Significant, but lower lod scores were found for 6q14 (1.2), 11p11 (1.5), and 19q13.4 (0.9), areas implicated in a previous genome wide study. Lod scores of 0.9 were obtained for both D78507, which lies 1 cM from the gammaT-cell receptor gene, and for D2S364, which lies 12 cM from the CTLA4 gene.
Abatacept↗
Should ambiguous trios for the TDT be discarded?
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Female↗
Association of specific chromosome alterations with tumour phenotype in posterior uveal melanoma.
Posterior uveal melanomas have recurrent alterations of chromosomes 1, 3, 6 and 8. In particular, changes of chromosomes 3 and 8 occur in association, appear to characterize those tumours with a ciliary body component, and have been shown to be of prognostic significance. The relevance of other chromosome alterations is less certain. We have performed cytogenetic analysis on 42 previously untreated primary posterior uveal melanomas. Of interest was the observation that as tumour size increased the involvement of specific chromosome changes, and the amount of chromosome abnormalities likewise increased. Loss, or partial deletions, of the short arm of chromosome 1 were found to associate with larger ciliary body melanomas; typically, loss of the short arm resulted from unbalanced translocations, the partners of which varied. Trisomy of chromosome 21 occurred more often in ciliary body melanomas, whilst rearrangements of chromosomes 6 and 11 were primarily related to choroidal melanomas. Our results imply that alterations of chromosome 1 are important in the progression of some uveal melanomas, and that other chromosome abnormalities, besides those of chromosomes 3 and 8, are associated with ocular tumours of particular locations.
Adult↗
Coeliac disease and Down syndrome: associations not due to genetic linkage on chromosome 21.
BACKGROUND: Individuals with Down syndrome have an increased prevalence of coeliac disease (CD). The HLA region accounts for only 30% of the heritability of CD, and segregation analyses have suggested the involvement of at least one other non-HLA gene. Distribution of known HLA susceptibility types in Down syndrome and normal populations are similar and do not explain the difference in disease frequency. This study tests the hypothesis that the association between these disorders is due to a susceptibility gene for coeliac disease being present on chromosome 21. METHODS: We studied 21 families multiply affected with CD, none of whom had Down syndrome. The typing information of six microsatellite markers across chromosome 21 was used to test linkage. RESULTS: Negative results from lod score and model-free linkage analysis were obtained, providing no support for genetic linkage of coeliac disease to chromosome 21 in this population. CONCLUSIONS: The high prevalence of coeliac disease in Down syndrome is not due to an increased copy number of a polymorphic susceptibility gene on chromosome 21.
Celiac Disease↗
Occlusal considerations in determining treatment prognosis.
To function in occlusal harmony, the masticatory apparatus--composed of the teeth and its supporting structures, temporomandibular joints, and associated neuromusculoskeletal structures--must operate in an integrated and dynamic manner. Loss of integrated function, or of homeostasis in response to functional demand, may generate problems in occlusion. In health, adaptive changes occur with the teeth and periodontium in response to functional occlusal forces. With periodontal and endodontic disease, this adaptive capacity diminishes. The ability to foresee how these changes may influence dental treatment is important in the art of determining treatment prognosis.
Adaptation, Physiological↗