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D Clayton

Publications and source records attributed to D Clayton.

At least 55 records · Page 3Linked to original sources
PubMed1997

Empirical genomewide significance levels established by whole genome simulations.

The advent of high-resolution genetic maps and semiautomated genotyping technology has opened the way for genome screening in genetically complex traits. Many such screens are now under way, or completed, most using multipoint nonparametric linkage analysis of affected sibling pairs. This type of linkage analysis uses all the available genotype information to calculate the maximum lod score (MLS) value at each point in the genome, and thereby generates MLS profiles along each chromosome. Any positive MLS values indicate potential linkage, but the peaks in these profiles, which may be referred to as "hits," identify the most likely locations of disease susceptibility genes. However, such analysis presents serious problems of multiple testing, and the assessment of the statistical significance of hits has become a contentious issue [Lander and Kruglyak (1995) Nat Genet 11:241-247; Curtis (1996) Nat Genet 12:356-357; Witte et al. (1996) Nat Genet 12:355-356]. Having recently completed a genome screen in multiple sclerosis, we decided to investigate the statistical properties of our study by simulation. We report here in detail the results of this simulation study. Our main conclusion is that, for the particular set of families and markers used in our screen, an MLS of 3.2 carries a genome-wide significance of 5% (that is, there is a 5% probability of observing at least one false hit, above this threshold in a complete genome screen). This value is closer to the familiar limit of 3.0, originally suggested by Morton [1955; Am J Hum Genet 7:277-318] than to the more stringent limit of 4.0 recently proposed by Lander and Kruglyak [1995; Nat Genet 11:241-247]. This is somewhat reassuring, in view of the very large sample sizes that would be necessary to achieve adequate power to detect linkage at the more stringent threshold.

Female↗
PubMed1997

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

Adult↗
PubMed1997

Analysis of the candidate gene NRAMP1 in the first 61 ARC National Repository families for rheumatoid arthritis.

Maximum likelihood identity-by-descent (IBD) sib pair analysis using a 3 locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum LOD score = 1.01, p = 0.024) for a gene in this region of human chromosome 2q35 contributing to susceptibility to rheumatoid arthritis (RA). Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p < 0.048) toward transmission of the NRAMP1 promoter region allele 3 in affected offspring.

Alleles↗
PubMed1996

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

OBJECTIVE: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. DESIGN: Correlative survey study of 477 MEN 2 families. SETTING: Eighteen tertiary referral centers worldwide. PATIENTS: A total of 477 independent MEN 2 families. MAIN OUTCOME MEASURES: Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. RESULTS: There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. CONCLUSIONS: This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Carcinoma, Medullary↗
PubMed1996

Childhood leukaemia in Europe after Chernobyl: 5 year follow-up.

The European Childhood Leukaemia - Lymphoma Incidence Study (ECLIS) is designed to address concerns about a possible increase in the risk of cancer in Europe following the nuclear accident in Chernobyle in 1986. This paper reports results of surveillance of childhood leukaemia in cancer registry populations from 1980 up to the end of 1991. There was a slight increase in the incidence of childhood leukaemia in Europe during this period, but the overall geographical pattern of change bears no relation to estimated exposure to radiation resulting from the accident. We conclude that at this stage of follow-up any changes in incidence consequent upon the Chernobyl accident remain undetectable against the usual background rates. Our results are consistent with current estimates of the leukaemogenic risk of radiation exposure, which, outside the immediate vicinity of the accident, was small.

Child↗
PubMed1996

A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22.

The population prevalence of multiple sclerosis is 0.1%; however, the risk of the disease in the siblings of affected individuals is very much higher at 3-5%. The importance of genetic factors in accounting for this increased risk is confirmed by the results of twin and adoption studies. Despite the evidence for a strong genetic effect, a weak major histocompatibility complex (MHC) association is the only consistently observed feature in the genetics of multiple sclerosis. Other candidates have been proposed, including genes encoding the immunoglobulin heavy chain, T cell receptor beta chain and APOC2, but none has yet been confirmed. Evidence for linkage and association to the myelin basic protein gene has been reported in a genetically isolated Finnish population, but it has not been possible to reproduce these results in other populations. We used a two-stage approach to search the human genome for the genes causing susceptibility to multiple sclerosis. Two principal regions of linkage are identified, chromosomes 17q22 and 6p21 (MHC). Our results are compatible with genetic models involving epistatic interaction between these and several additional genes.

Chromosome Mapping↗
PubMed1996

Age-adjusted recurrence risks for relatives of patients with multiple sclerosis.

Familial aggregation is a cardinal epidemiological feature of multiple sclerosis, but few investigators have systematically examined recurrence risks for relatives of affected individuals in the United Kingdom. As part of a cross-sectional study of multiple sclerosis in Cambridgeshire, pedigree details were taken on 674 probands. Sex-specific, crude and age-adjusted recurrence risks were assessed amongst relatives of probands, applying a statistical model based on the observed age at onset of affected individuals and providing risks for clinical counselling. Details on year of birth, present age or age at death, and disease status were available on 11 391 relatives of successive probands. Nineteen percent of patients reported an additionally affected relative; 128 non-proband affected relatives were identified and the highest risk was observed for sisters. There was a systematic reduction in relative risk with genetic distance from the proband and no preferential recurrence for maternal or paternal relatives.

Adult↗
PubMed1996

Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35.

The macrophage resistance gene NRAMP1 regulates priming/activation of macrophages for enhanced TNF alpha, IL 1 beta, and MHC class II expression. Since all of these functions are of potential importance in the induction or maintenance or both of autoimmune disease, samples from the Arthritis and Rheumatism Council's repository of multicase rheumatoid arthritis families were typed for a dinucleotide repeat in the NRAMP1 promoter region and four other 2q34 (TNP1) or 2q35 (IL8R, VIL1, DES) marker genes. Identity by descent (IBD) sib pair analysis using a three locus haplotype NRAMP1-IL8RB-VIL1, or NRAMP1 alone, provided preliminary evidence (maximum lod score = 1.01, p = 0.024) for a gene in this region contributing to suceptibility to rheumatoid arthritis. Candidacy for NRAMP1 as the disease susceptibility gene was supported by a significant bias (p = 0.048) towards transmission of the NRAMP1 promoter region allele 3 in affected offspring.

Arthritis, Rheumatoid↗
PubMed1996

CAMPATH-IH in multiple sclerosis.

In a pilot study, seven patients with multiple sclerosis were treated with CAMPATH-IH which targets the CD52 antigen present on lymphocytes and monocytes. There was a substantial reduction in disease activity as measured by gadoliunium-enhancing lesions on MRI. Encouraged by this result a further seven patients have been treated with CAMPATH-IH; four also received anti-CD4 antibody. Lymphopaenia developed rapidly and was sustained for at least one year. In 12 patients, the first infusion of antibody was characterised by significant exacerbation or re-awakening of pre-existing symptoms lasting several hours. These clinical effects of antibody treatment correlated with increased levels of circulating cytokines. Peak levels of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) occurred at 2 h whereas the rise in interleukin-6 (IL-6) was significantly delayed and peaked at 4 h after starting antibody treatment. The neurological symptoms could not be attributed directly to pyrexia and were not provoked (in one patient) by an artificial rise in temperature. In the remaining two patients, a single pre-treatment with intravenous methylprednisolone (500 mg) prevented both the transient increase in neurological symptoms and the cytokine release. Our results suggest that soluble immune mediators contribute to symptom production in multiple sclerosis by directly or indirectly blocking conduction through partially demyelinated pathways.

Adrenal Cortex Hormones↗
PubMed1996

Clinical concordance in sibling pairs with multiple sclerosis.

As part of a linkage study, we obtained clinical, demographic, and genetic information on 210 families with siblings concordant for multiple sclerosis (MS). Twenty-eight pairs were excluded and information was incomplete in a further 16 pairs; intrafamilial comparisons of the clinical course are reported on the remaining 166 families (155 pairs and 11 trios) in whom complete data sets were available. The demographic characteristics were comparable to those of recently performed prevalence studies in the United Kingdom, supporting the application of results in these families for genetic linkage studies in MS. We observed no significant correlation for age at onset after correction for selection bias but found a minor correlation for year at onset, which we speculate is due to earlier recognition of symptoms in second affected siblings. There was no pair-wise concordance for presenting symptoms or disability at time of assessment. However, there was a strong correlation for disease course and to a lesser degree for gender. In addition, the familial recurrence rate was 33%, almost twice that previously recorded in a local prevalence study. These results suggest that the etiology of MS involves random exposure to an, as yet unidentified, environmental trigger and the clinical features of familial disease are modified by inherited factors. That the risk of developing MS is not spread uniformly among families has important implications for the counseling of individuals with familial disease.

Female↗
PubMed1995

Genome scan for association and linkage.

In this paper, a genome search is performed on the GAW Problem 1 data, in an attempt to determine which, if any, of the marker loci are associated and/or linked with the disease. Since there was no clear indication from the data of the likely mode of inheritance, methods were used which did not require such assumptions to be made. A two-stage procedure was used to test for association. Firstly a standard unmatched case-control test was applied to all the loci. The family-based method of Self et al. [1991] was then applied to those loci which gave a positive result in the first stage. This procedure correctly detected loci 1 and 2, and that disease risk was increased for homozygote carriers of the disease allele at each locus, although a false positive result was also found. The affected sib pair method of Holmans [1993] was also applied to the data, although the sample contained far too few sib-pairs for such an analysis to be effective. This analysis failed to find any of the disease loci.

Case-Control Studies↗
PubMed1995

Susceptibility to multiple sclerosis and the immunoglobulin heavy chain variable region.

A haplotype marker consisting of three biallelic restriction fragment length polymorphism (RFLP) loci from the VH-2 variable gene family was examined in 124 families with sibling pairs concordant for multiple sclerosis, 178 unrelated patients and 159 unaffected controls to investigate the role of the immunoglobulin heavy chain gene cluster in susceptibility to multiple sclerosis. Evidence for linkage was assessed using the affected sibling pair method of identity by descent, modified to allow for haplotype sharing on a probabilistic basis in families where haplotypes could not be assigned with certainty. The estimated probabilities of affected siblings sharing 0, 1 or 2 haplotypes were Z0 = 0.20, Z1 = 0.45, Z2 = 0.35. This deviation from the expected sharing probabilities of Z0 = 0.25, Z1 = 0.5, Z2 = 0.25 provides evidence for weak linkage (P < 0.05; equivalent to a lod score of 0.84); however, no significant allelic or haplotypic association was observed. Linkage without a population association suggests that a gene encoded on 14q confers susceptibility to multiple sclerosis, although this is not any of the existing VH-2 polymorphisms.

Alleles↗
PubMed1995

Multiple sclerosis and the HLA-D region: linkage and association studies.

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.

Adult↗
PubMed1995

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

BRCA1 Protein↗
PubMed1995

The T-cell receptor beta locus and susceptibility to multiple sclerosis.

Assessments of genetically determined variations in the T-cell antigen receptor in multiple sclerosis (MS) have yielded conflicting results. We used three restriction fragment length polymorphisms (RFLPs) and a polymorphic microsatellite repeat as markers for the T-cell receptor (TCR) beta locus (7q32-35) in multiplex MS families. Affected sibling-pair analysis of the RFLP data failed to show evidence for linkage (127 families) whereas analysis of the microsatellite data (86 families) provided weak evidence for linkage with a maximum lod score of 0.98 (p < 0.05). We repeated the analysis in those families (n = 53) in which the affected sibling pairs were concordant for the HLA haplotype DR15/DQ6. This altered the proportion of affected siblings sharing 0, 1, 2 RFLP haplotypes from 0.24, 0.50, and 0.26 (p = NS) before stratification to 0.16, 0.41, and 0.43 (p < 0.05) in the DR15/DQ6 positive pairs alone; for the microsatellite data, sharing altered from 0.16, 0.50, and 0.34 (p < 0.05) in all pairs to 0.07, 0.49, and 0.44 (p < 0.01) in the DR15/DQ6 concordant siblings.

Adult↗
PubMed1995

Repeated exposure to one song leads to a rapid and persistent decline in an immediate early gene's response to that song in zebra finch telencephalon.

Conspecific song induces a prompt increase in the expression of the zenk gene in the caudo-medial neostriatum (NCM), a part of the auditory telencephalon of songbirds. To test the hypothesis that zenk gene induction in NCM is related to the acquisition of new song-related memories, we presented adult male zebra finches with repeated playbacks of one song. In response, zenk mRNA levels in NCM increased for the first 30 min, but then declined back to baseline levels despite continued stimulation with the same song. When a novel song was then introduced, however, a full zenk response was triggered once again. Even when a full day had passed between the last exposure to a song and the testing period, the song that had been rendered "familiar" by repetition caused no zenk response, whereas a novel song caused a full response. Quantitative analysis indicates that individual cells in NCM must have undergone a selective loss in their zenk responsiveness to the repeated song, while still maintaining their ability to respond to the novel song. These results support the hypothesis that the induction of zenk is related to the formation of long-term memories. Analysis of the stimulus-specific modulation of zenk responses, coupled with appropriate behavioral assays, should provide insight into neural mechanisms responsible for the discrimination and storage of complex perceptual information.

Animal Communication↗
PubMed1995

Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers.

In an affected-sib-pair study, the parents are often unavailable for typing, particularly for diseases of late onset. In many cases, however, it is possible to sample unaffected siblings. It is therefore desirable to assess the contribution of such siblings to the power of such a study. The likelihood ratio introduced by Risch and improved by Holmans was extended to incorporate data from unaffected siblings. Tests based on two likelihoods were considered: the full likelihood of the data, based on the identity-by-descent (IBD) sharing states of the entire sibship, and a pseudolikelihood based on the IBD sharing states of the affected pair only, using the unaffected siblings to infer parental genotypes. The latter approach was found to be more powerful, except when penetrance was high. Typing an unaffected sibling, or just one parent, was found to give only a small increase in power except when the PIC of the marker was low. Even then, typing an unaffected relative increased the overall number of individuals that had to be typed to achieve a given power. If there is no highly informative marker locus in the area under study, it may be possible to "build" one by combining the alleles from two or more neighboring tightly linked loci into haplotypes. Typing two loci gave a sizeable power increase over a single locus, but typing further loci gave much smaller gains. Building haplotypes will introduce phase uncertainties, with the result that such a system will yield less power than will a single locus with the same number of alleles. This power loss was small, however, and did not affect the conclusions regarding the worth of typing unaffected relatives.

Alleles↗