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At least 325 records · Page 18Linked to original sources
PubMed1990

Identification of a hypervariable microsatellite polymorphism within D9S15 tightly linked to Friedrich's ataxia.

We have identified a hypervariable microsatellite sequence within the chromosome 9 marker MCT112 (D9S15), which we have previously shown to be tightly linked to Friedreich's ataxia (FRDA). The system detects 7 alleles ranging in size from 195 to 209 base pairs, and substantially increases informativity at the MCT112 locus. This enhances its use for genetic counselling in affected families. Recalculated combined linkage data between the FRDA locus and MCT112 gives a maximal lod score of 66.91 at a recombination fraction of theta = 0). There is no evidence of linkage disequilibrium.

Alleles↗
PubMed1996

Localisation of a new gene for non-specific mental retardation to Xq22-q26 (MRX35).

Non-specific mental retardation (MR) is a condition in which MR appears to be the only consistent manifestation. The X linked form (MRX) is genetically heterogeneous. We report clinical, cytogenetic, and linkage data on a family with X linked non-specific MR. Two point and multi-point linkage analysis with 18 polymorphic markers, covering the entire chromosome, showed close linkage to DXS1001 and DXS425 with a maximal lod score of 2.41 at 0% recombination. DXS178 and the gene for hypoxanthine phosphoribosyl-transferase (HPRT), located in Xq22 and Xq26 respectively, flank the mutation. All other chromosomal regions could be excluded with odds of at least 100:1. To our knowledge there is currently no other non-specific MR gene mapped to this region. Therefore, the gene causing MR in this family can be considered to be a new, independent MRX locus (MRX35).

Child↗
PubMed1993

Genetic maps of the sheep blowfly Lucilia cuprina: linkage-group correlations with other dipteran genera.

Linkage data and revised genetic maps for 72 autosomal loci in Lucilia cuprina are presented. Comparison of the linkage relationships of biochemically and morphologically similar mutations in Ceratitis capitata, Drosophila melanogaster, and Musca domestica supports the hypothesis that the major linkage elements have survived relatively intact during evolution of the higher Diptera. The relationship of the linkage groups of the mosquito Aedes aegypti to these species is less clear.

Aedes↗
PubMed1992

Confirmation and refinement of the genetic localization of the Coffin-Lowry syndrome locus in Xp22.1-p22.2.

The Coffin-Lowry syndrome (CLS) is an X-linked inherited disease of unknown pathogenesis characterized by severe mental retardation, typical facial and digital anomalies, and progressive skeletal deformations. Our previous linkage analysis, based on four pedigrees with the disease, suggested a localization for the CLS locus in Xp22.1-p22.2, with the most likely position between the marker loci DXS41 and DXS43. We have now extended the study to 16 families by using seven RFLP marker loci spanning the Xp22.1-p22.2 region. Linkage has been established with five markers from this part of the X chromosome: DXS274 (lod score [Z] (theta) = 3.53 at theta = .08), DXS43 (Z(theta) = 3.16 at theta = .08), DXS197 (Z(theta) = 3.03 at theta = .05), DXS41 (Z(theta) = 2.89 at theta = .08), and DXS207 (Z(theta) = 2.73 at theta = .13). A multipoint linkage analysis further placed, with a maximum multipoint Z of 7.30, the mutation-causing CLS within a 7-cM interval defined by the cluster of tightly linked markers (DXS207-DXS43-DXS197) on the distal side and by DXS274 on the proximal side. Thus, these further linkage data confirm and refine the map location for the gene responsible for CLS in Xp22.1-p22.2. As no linkage heterogeneity was detected, this validates the use of the Xp22.1-p22.2 markers for carrier detection and prenatal diagnosis in CLS families.

Abnormalities, Multiple↗
PubMed1998

Comprehensive HLA-DP typing using polymerase chain reaction with sequence-specific primers and 95 sequence-specific primer mixes.

HLA-DP is the third of the class II molecules. Its role is antigen presentation, and it has been suggested to play a part in the susceptibility to certain diseases such as berylliosis, sarcoidosis and juvenile chronic arthritis. The standard typing method is SSO typing, although other methods have been used. Probably the best is sequence-based typing, but this is time-consuming and requires expensive equipment. We describe a method for comprehensive HLA-DPB1 and HLA-DPA1 typing using sequence-specific primers. This method has the advantages that it is rapid - typing a single DNA sample takes under 3 hours - and does not require any special equipment or reagents. The method has been shown to be highly accurate by typing 60 cell line DNA samples in which there was 100% agreement between the types obtained and the published information. Similarly typing of 20 DNA samples previously typed by sequence-based typing gave 100% concordance. We used the method to type DNA samples from 102 UK Caucasoid kidney donors. The allele frequencies agree with previously published data. Linkage disequilibria between HLA-DPB1, HLA-DPA1 and the other class II antigens have been investigated. Strong linkage disequilibria exist between certain HLA-DPB1 and HLA-DPA1 alleles. This is unsurprising in view of their proximity on the chromosome. More unexpectedly, the data also suggest that genes further away along the chromosome are in linkage disequilibrium with HLA-DP, forming extended haplotypes.

DNA Primers↗
PubMed2005

Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease.

We previously reported a linkage region on chromosome 1p (LOD = 3.41) for genes controlling age at onset (AAO) in Parkinson disease (PD). This region overlaps with the previously reported PARK10 locus. To identify the gene(s) associated with AAO and risk of PD in this region, we first applied a genomic convergence approach that combined gene expression and linkage data. No significant results were found. Second, we performed association mapping across a 19.2-Mb region centered under the AAO linkage peak. An iterative association mapping approach was done by initially genotyping single-nucleotide polymorphisms at an average distance of 100 kb apart and then by increasing the density of markers as needed. Using the overall data set of 267 multiplex families, we identified six associated genes in the region, but further screening of a subset of 83 families linked to the chromosome 1 locus identified only two genes significantly associated with AAO in PD: the gamma subunit of the translation initiation factor EIF2B gene (EIF2B3), which was more significant in the linked subset and the ubiquitin-specific protease 24 gene (USP24). Unexpectedly, the human immunodeficiency virus enhancer-binding protein 3 gene (HIVEP3) was found to be associated with risk for susceptibility to PD. We used several criteria to define significant results in the presence of multiple testing, including criteria derived from a novel cluster approach. The known or putative functions of these genes fit well with the current suspected pathogenic mechanisms of PD and thus show great potential as candidates for the PARK10 locus.

Adolescent↗
PubMed1987

Genetic models for linkage analysis of ataxia-telangiectasia.

Ataxia-telangiectasia (AT) is a multifaceted autosomal recessive disorder, inherited as a single gene in each family, presumably due to a defective DNA processing protein such as a recombinase, endonuclease or even a regulatory DNA-binding protein. We are attempting to identify the chromosomal location of the AT gene(s) by performing linkage analyses on a variety of genetic models. At least five AT complementation groups have been defined. This genetic heterogeneity complicates linkage analysis. Model I assumes that the complementation genes are clustered into a single genomic region and, therefore, lod scores of linkage data from all families can be added. Model II assumes that the AT complementation genes are dispersed throughout the genome and the lod scores cannot be added. This model necessitates assigning the complementation group of every family that is included in the linkage analyses and reduces the number of families in each data base. Model III utilizes heterozygote identification to follow the AT gene (in a Group A pedigree of 61 members) as a dominant trait, thereby increasing the amount of linkage information that can be derived from that family. Model IV will focus only on consanguineous offspring of first-cousin marriages, seeking to identify the location of the AT gene(s) by the increased degree of homozygosity of genetic markers in close proximity. This model has several advantages, including that much smaller numbers of patients are required. Model V assumes that a subset of our patients will carry deletions and can be used to confirm the relationship of a candidate gene to the AT phenotype. Progress: Models I and II have been used to survey 7% and 2% of the genome, respectively. (An additional 5% of the genome can be added for exclusion of the X chromosome on clinical grounds). Model III is intended to survey the entire genome. Our initial studies have surveyed approximately 30% of the genome. Several areas of increased lod scores have been identified and are under further investigation.

Ataxia Telangiectasia↗
PubMedDate not supplied

A checklist for retrospective database studies--report of the ISPOR Task Force on Retrospective Databases.

INTRODUCTION: Health-related retrospective databases, in particular claims databases, continue to be an important data source for outcomes research. However, retrospective databases pose a series of methodological challenges, some of which are unique to this data source. METHODS: In an effort to assist decision makers in evaluating the quality of published studies that use health-related retrospective databases, a checklist was developed that focuses on issues that are unique to database studies or are particularly problematic in database research. This checklist was developed primarily for the commonly used medical claims or encounter-based databases but could potentially be used to assess retrospective studies that employ other types of databases, such as disease registries and national survey data. RESULTS: Written in the form of 27 questions, the checklist can be used to guide decision makers as they consider the database, the study methodology, and the study conclusions. Checklist questions cover a wide range of issues, including relevance, reliability and validity, data linkages, eligibility determination, research design, treatment effects, sample selection, censoring, variable definitions, resource valuation, statistical analysis, generalizability, and data interpretation. CONCLUSIONS: For many of the questions, key references are provided as a resource for those who want to further examine a particular issue.

Data Interpretation, Statistical↗
PubMed1995

Localization of a gene for X-linked nonspecific mental retardation (MRX24) in Xp22.2-p22.3.

Nonspecific X-linked mental retardation (MRX) includes several distinct genetic entities in which mental retardation is not associated with additional distinguishing physical changes. We report linkage data in a Spanish family with MRX, using polymorphic DNA markers distributed over the X chromosome. Two-point linkage analysis demonstrated close linkage between the MRX locus and DXS85 in Xp22.3 with a peak lod score of 2.28 at a theta = 0.00. Analysis of multiple informative meioses suggested a localization of the MRX locus (MRX24) between DXS278 and DXS207. Multipoint linkage analysis resulted in a maximum LOD score of 2.45 at 3 cM proximal to DXS85, and allowed us to reject a localization of the MRX24 gene in all other regions from Xp21-Xqter. These findings localize the MRX24 gene in the chromosomal region Xp22.2-p22.3.

Chromosome Mapping↗
PubMed1982

A new genetic variation of the malate dehydrogenase-like enzyme (MDL-1) in inbred rats and its possible linkage.

A new polymorphism in the mitochondrial fraction of kidney homogenates was found by using discontinuous polyacrylamide gel electrophoresis. The polymorphism is tentatively designated MDL-1, since the enzyme was visualized with the staining solution for NADP-malate dehydrogenase (MOD) but differs from MOD. MDL-1 expresses three phenotypes: MDL-1A (fast), MDL-1AB (intermediate), and MDL-1B (slow). Progeny testing from genetic crosses indicates that its expression is determined by two codominant alleles, Mdl-1a and Mdl-1b, which segregate in a simple Mendelian fashion. Preliminary linkage data suggest that the locus for MDL-1 is probably linked to the nonagouti-agouti locus in rat linkage group IV.

Alleles↗
PubMed2006

Attempted suicide in bipolar disorder pedigrees: evidence for linkage to 2p12.

BACKGROUND: We are interested in identifying susceptibility genes that predispose subjects to attempted suicide. METHODS: We conducted a secondary analysis of genome-wide linkage data from 162 bipolar pedigrees that incorporated attempted suicide as a clinical covariate. RESULTS: The strongest covariate-based linkage signal was seen on 2p12 at marker D2S1777. The logarithm of odds (LOD) score at marker D2S1777 rose from 1.56 to 3.82 after inclusion of the suicide covariate, resulting in significant chromosome-wide empirically derived p-values for the overall linkage finding (p = .01) and for the change in LOD score after the inclusion of the covariate (p = .02). CONCLUSIONS: The finding on chromosome 2 replicates results from two previous studies of attempted suicide in pedigrees with alcohol dependence and in pedigrees with recurrent early-onset depression. Combined, these three studies provide compelling evidence for a locus influencing attempted suicide on 2p12.

Bipolar Disorder↗
PubMed2005

Genomic approaches to schizophrenia.

BACKGROUND: Genetic epidemiologic studies suggest that individual variation in susceptibility to schizophrenia is substantially genetic. However, like other common disorders, the mode of transmission is complex and probably reflects oligogenic inheritance against a polygenic background. OBJECTIVE: The goal of this article was to introduce genomics as an approach to understanding the causes of schizophrenia. CONCLUSIONS: Genomic approaches to schizophrenia are becoming increasingly feasible as data from the Human Genome Project accumulate and technology improves. Attempts to identify genes for schizophrenia have been based on 4 main approaches: genetic linkage studies, studies of chromosomal abnormalities associated with the disorder, association studies, and convergent genomics. Several strong linkages have been found, and there is emerging consensus regarding at least some of the chromosomal regions likely to contain schizophrenia genes. However, moving from linked region to susceptibility gene is still difficult, given our poor understanding of the pathophysiology and population genetics, and the complexity of the phenotype. Despite this difficulty, positional candidate genes have been identified, and in 2 instances-neuregulin 1 and dysbindin-1-support has come from several studies. The rates of schizophrenia seen in individuals with deletions of chromosome 22q11, as well as linkage data,suggest that this chromosomal region might contain a susceptibility locus.

Chromosome Aberrations↗
PubMed1996

A method for determining familial cancer risks in clinical practice.

There is interest in estimating familial cancer risks in clinical practice for counselling and determining patients' screening requirements. Empiric methods can be used to estimate an individual's risk, however, every family history is unique making such methods relatively non-specific. In contrast if an underlying genetic model can be assumed the risk of disease can be calculated for any individual using his or her family history. A method of estimating familial cancer risks based on segregation models and linkage data is presented and its implementation discussed.

Genetic Linkage↗
PubMed1989

Linkage analyses of human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B).

Linkage data on human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B) are presented. The results confirm linkage between HF and F13B (lod = 5.32 at theta = 0.10 in males), and give strong evidence for linkage between PEPC and HF (lod = 5.14 at theta = 0.10 in males) and between PEPC and F13B (lod = 3.55 at theta = 0.10 in males). The claim that PEPA is linked with HF must be withdrawn.

Complement C3b Inactivator Proteins↗
PubMed1992

Multipoint mapping of adult onset polycystic kidney disease (PKD1) on chromosome 16.

Analysis of genetic linkage data in 33 adult onset polycystic kidney (ADPKD) families was carried out using probes for the D16S85, D16S84, and D16S94 loci. The data set of 33 families shows no evidence of genetic heterogeneity since one unlinked family was previously excluded. Two point linkage analysis showed maximum likelihood values of the recombination fraction of 0.07 for ADPKD and D16S85 (lod score 18.78), 0.02 for ADPKD and D16S84 (lod score 7.55), and 0.00 for ADPKD and D16S94 (lod score 6.73). Multipoint analysis showed a maximum likelihood order of tel-D16S85-0.06-D16S84-0.02-(PKD1, D16S94)-cen with a multipoint lod score of 32.16. Analysis of rare recombinants lying close to PKD1 gave results consistent with this order.

Chromosome Mapping↗
PubMed1977

Total care usage of a defined population.

The North Staffordshire (Stoke) Morbidity Survey was set up to bring together data about the total use of general practice, hospital and local authority services by each individual patient in a representative sample of the population of Stoke, and to examine the associated problems of data linkage and confidentiality. Approximately 47.8 per cent (32.1 per cent if allowance is made for all measurable possible errors) of the patients attending hospital and 43.8 per cent of patients attending local authority services during the year, did not attend their general practitioner.Primary automation of the registered list of patients at risk is essential to the success of any automated linkage study. Where the list consists of Hogben numbers to identify individuals, this also ensures the necessary confidentiality of sensitive data.

Community Health Services↗
PubMed2006

Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus.

OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Adaptor Proteins, Signal Transducing↗
PubMed1997

The role of immunocytochemistry and linkage analysis in the prenatal diagnosis of merosin-deficient congenital muscular dystrophy.

Complete or partial deficiency of the laminin alpha2 chain of merosin has been demonstrated in a proportion of children with classical congenital muscular dystrophy and linkage to the laminin alpha2 chain gene (LAMA2) on chromosome 6q2 has been established. As the laminin alpha2 chain is also expressed in the trophoblast, its detection and linkage analysis are useful tools for prenatal diagnosis. We report our experience of seven prenatal diagnoses in families with partial deficiency or total absence of the laminin alpha2 chain in the muscle of the propositi. In five instances, expression of the laminin alpha2 chain in the trophoblast was normal and linkage data suggested that the fetuses were unaffected. In one family, the immunocytochemical studies of the trophoblast showed the absence of laminin alpha2, suggesting that the fetus was affected. Linkage analysis confirmed that the fetus had inherited the two at-risk haplotypes. In one family with partial laminin alpha2 chain deficiency, the haplotype analysis was hampered by maternal DNA contamination. Immunocytochemical analysis of chorionic villus sampling showed a reduction in laminin alpha2 expression. The pregnancy was presumed to be at high-risk and terminated. However, subsequent analysis of fetal DNA indicated that the fetus was probably heterozygous. Our data suggest that immunocytochemical analysis of the trophoblast can detect abnormalities in affected fetuses and gives normal results in unaffected and carrier fetuses. Nevertheless, we recommend that linkage analysis to the LAMA2 locus is also studied in all cases.

Female↗