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Biomedical subjects

D Curtis

Publications and source records attributed to D Curtis.

At least 127 records · Page 7Linked to original sources
PubMed1995

Monte Carlo tests for associations between disease and alleles at highly polymorphic loci.

In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi-squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.

Alleles↗
PubMed1995

Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior.

OBJECTIVE: Previous studies have demonstrated a relationship between obsessive-compulsive disorder or behavior and Gilles de la Tourette syndrome. It has been hypothesized that the serotonergic system is implicated in the etiology of obsessive-compulsive disorder. Therefore, the authors investigated whether genetic variation in a serotonergic receptor and a modifying enzyme were associated with Tourette's syndrome. METHOD: A linkage analysis using DNA and blood group markers was carried out in a large British kindred multiply affected with Tourette's syndrome, chronic motor tics, and obsessive-compulsive behavior. RESULTS: There was no evidence to support the hypothesis that genetic variation in the serotonin 5-HT1A receptor and tryptophan oxygenase genes causes susceptibility to Tourette's syndrome and chronic multiple tics. CONCLUSIONS: The results eliminate two possible candidate genes from having a role in the pathophysiology of Tourette's syndrome.

Female↗
PubMed1995

Investigation by linkage analysis of the XY pseudoautosomal region in the genetic susceptibility to schizophrenia.

BACKGROUND: A susceptibility locus for schizophrenia in the pseudoautosomal region has been proposed on the basis of a possible excess of sex chromosome aneuploidies among patients with schizophrenia and an increased sex concordance in affected sib pairs. Several studies investigating this hypothesis have produced conflicting evidence. METHOD: In a series of Icelandic and British families, we used lod score and sib pair linkage analyses with markers for the MIC2 and DXYS14 loci on the pseudoautosomal XY region. RESULTS: Lod and sib pair linkage analysis with these markers produced strongly negative scores. Heterogeneity testing also produced negative results. CONCLUSION: We conclude that the present study provides no support for the involvement of either the pseudoautosomal region or the nearby region of the sex chromosomes in the aetiology of schizophrenia.

Aneuploidy↗
PubMed1995

nanos is an evolutionarily conserved organizer of anterior-posterior polarity.

In Drosophila melanogaster, nanos functions as a localized determinant of posterior pattern. Nanos RNA is localized to the posterior pole of the maturing egg cell and encodes a protein that emanates from this localized source. Nanos acts as a translational repressor and thereby establishes a gradient of the morphogen Hunchback. Here we show that the mechanism by which nanos acts in Drosophila is a common developmental strategy in Dipteran insects. We used cytoplasmic transplantation assays to demonstrate that nanos activity is found in posterior poleplasm of five diverse Dipteran species. Genes homologous to nanos were identified from Drosophila virilis, the housefly Musca domestica, and the midge Chironomus samoensis. These genes encode RNAs that are each localized, like nanos, to the embryonic posterior pole. Most importantly, we demonstrate that these homologues can functionally substitute for nanos in D. melanogaster. These results suggest that nanos acts in a similar pathway for axis determination in other insects. Comparison of the Nanos sequences reveals only 19% overall protein sequence similarity; high conservation of a novel zinc finger near the carboxy terminus of the protein defines a region critical for nanos gene function.

Amino Acid Sequence↗
PubMed1995

Model-free linkage analysis using likelihoods.

Misspecification of transmission model parameters can produce artifactually negative lod scores at small recombination fractions and in multipoint analysis. To avoid this problem, we have tried to devise a test that aims to detect a genetic effect at a particular locus, rather than attempting to estimate the map position of a locus with specified effect. Maximizing likelihoods over transmission model parameters, as well as linkage parameters, can produce seriously biased parameter estimates and so yield tests that lack power for the detection of linkage. However, constraining the transmission model parameters to produce the correct population prevalence largely avoids this problem. For computational convenience, we recommend that the likelihoods under linkage and non-linkage are independently maximized over a limited set of transmission models, ranging from Mendelian dominant to null effect and from null effect to Mendelian recessive. In order to test for a genetic effect at a given map position, the likelihood under linkage is maximized over admixture, the proportion of families linked. Application to simulated data for a wide range of transmission models in both affected sib pairs and pedigrees demonstrates that the new method is well behaved under the null hypothesis and provides a powerful test for linkage when it is present. This test requires no specification of transmission model parameters, apart from an approximate estimate of the population prevalence. It can be applied equally to sib pairs and pedigrees, and, since it does not diminish the lod score at test positions very close to a marker, it is suitable for application to multipoint data.

Chromosome Mapping↗
PubMed1994

A linkage study of affective disorder with DNA markers for the ABO-AK1-ORM linkage group near the dopamine beta hydroxylase gene.

Combining data from a number of studies has provided evidence for a susceptibility allele for affective disorder near to the ABO-AK1-ORM region on chromosome 9q34. The dopamine beta hydroxylase gene locus is also at 9q34. Five multigenerational families with bipolar and unipolar affective disorder were analyzed for linkage with highly polymorphic microsatellite markers from the candidate region. The segregation of the illness in these families was compatible with an autosomal dominant susceptibility allele. Linkage analyses using conservative parameters seemed to provide strong evidence against a major susceptibility allele in this region including the candidate gene dopamine beta hydroxylase in these families.

ABO Blood-Group System↗
PubMed1994

Translational repression as a conserved mechanism for the regulation of embryonic polarity.

The mechanisms used to establish embryonic polarity are still largely unknown. A recent paper(1) describes the expression pattern of the gene glp-1, which is required for induction events during development of the nematode Caenorhabditis elegans. Although glp-1 RNA is found throughout the early embryo, Glp-1 protein is only expressed in anterior cells. This negative translational regulation in posterior cells is shown to be mediated through sequences in the glp-1 3'untranslated region (3'UTR). Thus in nematodes, as in Drosophila, translational repression is one mechanism used to establish the embryonic anterior-posterior axis.

Animals↗
PubMed1994

Linkage analysis of idiopathic generalised epilepsy in families of probands with Juvenile Myoclonic Epilepsy and marker loci in the region of EPM 1 on chromosome 21 q: Unverricht-Lundborg disease and JME are not allelic variants.

The locus for Unverricht-Lundborg disease, EPM 1, has recently been mapped to chromosome 21q22.3. A locus, EJM 1, predisposing to idiopathic generalised epilepsy in families of probands with juvenile myoclonic epilepsy has been localised to chromosome 6p by evidence of linkage to the HLA region. However, segregation analysis suggests a two-locus model for JME and evidence has been obtained for genetic heterogeneity within the JME/IGE phenotype. EPM 1 was therefore investigated as a candidate locus in the set of families segregating for IGE and JME which do not show linkage to markers on chromosome 6p. Linkage analysis was carried out in 25 families using three microsatellite DNA markers around the EPM 1 gene region using different models of inheritance. Multipoint linkage analysis provided definite exclusion for 20cM around PFKL, the closet linked marker to EPM 1, under three out of four models tested. These results strongly suggest that the EPM 1 gene is not linked to the phenotype expressed in these families, and therefore that Unverricht-Lundborg disease and juvenile myoclonic epilepsy are not allelic variants.

Adolescent↗
PubMed1994

The Marfan syndrome gene locus as a favoured locus for susceptibility to schizophrenia.

Marfan syndrome (MS) is a rare autosomal dominant disorder of connective tissue with manifestations in the cardiovascular, ocular and skeletal systems. Genetic linkage analysis with random probes has mapped the MS locus to 15q21.1. There have been several reports of Marfan syndrome co-segregating with schizophrenia within families, which suggest that a common genetic factor may be shared between schizophrenia susceptibility and MS. This could be due to a cytogenetic abnormality affecting both genetic loci or due to co-segregation of two disease loci near each other on the same chromosome. We tested this hypothesis by using genetic linkage analysis with multiplex families. Using three genetic markers spanning the MS locus, we were unable to find evidence of linkage with schizophrenia across the Marfan syndrome locus on chromosome 15.

Chromosomes, Human, Pair 15↗
PubMed1994

Another procedure for the preliminary ordering of loci based on two point lod scores.

Because of the difficulty of performing full likelihood analysis over multiple loci and the large numbers of possible orders, a number of methods have been proposed for quickly evaluating orders and, to a lesser extent, for generating good orders. A new method is proposed which uses a function which is moderately laborious to compute, the sum of lod scores between all pairs of loci. This function can be smoothly minimized by initially allowing the loci to be placed anywhere in space, and only subsequently constraining them to lie along a one-dimensional map. Application of this approach to sample data suggests that it has promise and might usefully be combined with other methods when loci need to be ordered.

Chromosome Mapping↗
PubMed1994

Using risk calculation to implement an extended relative pair analysis.

A new nonparametric method of linkage analysis is described based on identity by descent relationships between all pairs of affected relatives within a pedigree. This approach is an extension of ESPA, which only uses information from pairs of affected siblings. The new method, called ERPA, uses the risk calculation facilities of the LINKAGE programs to obtain the necessary information in a fashion which is simple to implement and which automatically generalizes to allow for marker loci which may be multiple, non-codominant and sex-linked. We have investigated the relative performance of ERPA, ESPA and the lod score method on simulated data. ERPA appears to be more sensitive than ESPA for detecting linkage in pedigrees with small sibships, though both nonparametric methods are inferior to the lod score method when the true mode of transmission can be specified.

Alleles↗
PubMed1994

Elevated serum homocysteine as a predictor for vitamin B12 or folate deficiency.

Tissue deficiency of vitamin B12 and folate results in an increase in serum homocysteine (sHcy). We have measured sHcy in patients with reduced serum vitamin B12 and/or red cell folate (RCF) to determine its usefulness as a discriminant for the diagnostic interpretation of reduced vitamin levels. Of 3846 patients who had serum vitamin B12 and RCF assayed, 335 (9%) had reduced vitamin levels. Multivariate analysis showed a significant association between sHcy and serum creatinine (p = 0.0001), positive intrinsic factor (IF) antibody or neutrophil hypersegmentation (NHS) (p = 0.001), increased MCV (p = 0.014) and low RCF (p = 0.025) but no relationship with the level of serum vitamin B12 or haemoglobin. After censoring the patients with renal impairment (n = 54), the distribution of the remaining 72 patients with elevated sHcy was 37/151 (25%) with low serum vitamin B12 with or without low RCF and 35/130 (27%) with low RCF alone. sHcy correctly identified response to vitamin therapy in 33/35 (94%) patients who had adequate parameters to assess response. The positive predictive values of IF antibody/NHS, macrocytosis and/or low RCF for elevated sHcy were 100% and 34% respectively. Twenty-four percent of patients with a low serum vitamin B12 and elevated sHcy had no abnormal haematologic parameters as determined by the routine laboratory staff. These data suggest that the usefulness of measuring sHcy in a routine diagnostic setting is limited and a careful review of the peripheral blood for macrocytosis and NHS plus determination of RCF may be a more cost-effective process than sHcy assay in most instances to determine the presence of tissue deficiency.

Adult↗
PubMed1993

Linkage between tyrosine hydroxylase gene and affective disorder cannot be excluded in two of six pedigrees.

Genetic linkage between manic depression and DNA markers on the short arm of chromosome 11 was first reported in 1987 but not supported by further analyses. However, genetic markers at the tyrosine hydroxylase (TH) gene located within this region have been reported to show allelic association with the affective disorder phenotype. We present the results of a linkage analysis using polymorphic DNA segments within the TH gene and the nearby dopamine D4 receptor (DRD4) gene in 6 families multiply affected with affective disorder. Small positive Lod scores were obtained in 2 of 6 pedigrees with the TH polymorphism which may be indicative of genetic heterogeneity.

Female↗
PubMed1993

Cloning of the human dopamine D5 receptor gene and identification of a highly polymorphic microsatellite for the DRD5 locus that shows tight linkage to the chromosome 4p reference marker RAF1P1.

We identified a cosmid clone with exact sequence homology to part of the human dopamine D5 receptor gene (DRD5) after screening a cosmid library with the human DRD1 gene. The dopamine D5 receptor was mapped to chromosome 4p15.1-p15.3 by in situ hybridization and using a somatic cell hybrid panel. We report here the further localization of the DRD5 gene following identification of a highly polymorphic dinucleotide repeat sequence in the cosmid clone. The microsatellite (D5(CT/GT/GA)n) had 12 alleles with a polymorphic information content value of 0.77. Linkage analysis in 39 CEPH pedigrees demonstrated tight linkage to the chromosome 4p reference marker RAF1P1 (Zmaxf 20.66 at theta f 0.05 and ZmaxM 16.57 at theta m 0.07).

Base Sequence↗