Search PubMed⌕ Search

Biomedical subjects

D E Weeks

Publications and source records attributed to D E Weeks.

At least 37 records · Page 2Linked to original sources
PubMed2000

Comparison of allele-sharing statistics for general pedigrees.

The popularity of "non-parametric" linkage analysis using moderate and large sized pedigrees has increased in the last few years. Only a few of the existing allele-sharing statistics are applicable to general pedigrees, and even fewer are in common use. Little research has been done to compare the power of these statistics. We present some preliminary investigations into the power of the most popular general-pedigree allele-sharing statistics. We show that there are indeed non-trivial differences among the statistics, and that further studies are warranted. In particular, pedigree structure and the degree of recessiveness of the trait appear to be critical factors in determining which statistics are most powerful.

Alleles↗
PubMed1999

Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium.

Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study on the collection of families from the International Molecular Genetic Study of Autism (IMGSA) Consortium, using the transmission disequilibrium test. Two polymorphisms in the 5-HTT gene (a functional insertion-deletion polymorphism in the promoter and a variable number tandem repeat in the second intron) were examined in 90 families comprising 174 affected individuals. Furthermore, seven microsatellite markers spanning the 15q11-q13 region were studied in 94 families with 182 affected individuals. No significant evidence of association or linkage was found at any of the markers tested, indicating that the 5-HTT and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set.

Autistic Disorder↗
PubMed1999

A comparison of two algorithms, MultiMap and gene mapping system, for automated construction of genetic linkage maps.

Using the GAW11 Problem 2 data set, we compared the performance of two automated map construction algorithms, MultiMap and GMS (Gene Mapping System). The MultiMap algorithm iteratively adds markers in a stepwise manner to the map, while the GMS algorithm seeks to find the best order of the whole set of markers by selective permutations of logically formed subgroups of the markers. While it is difficult to compare these two rather different algorithms, we found that, on these data, GMS performed better than MultiMap, placing more markers in their true order on average, with little order ambiguity. In addition, as the number of markers increased, GMS was less computationally demanding than MultiMap. However, it MultiMap placed a marker, it was almost always in the correct order. In contrast, GMS often placed a group of markers on the wrong end of the map; such incorrect placements occur when the evidence for placement on one end or the other is not strong. Thus, there is room for further algorithmic developments that combine the strengths of both the MultiMap and GMS approaches.

Algorithms↗
PubMed1999

A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia.

Recent application of nonparametric-linkage analysis to reading disability has implicated a putative quantitative-trait locus (QTL) on the short arm of chromosome 6. In the present study, we use QTL methods to evaluate linkage to the 6p25-21.3 region in a sample of 181 sib pairs from 82 nuclear families that were selected on the basis of a dyslexic proband. We have assessed linkage directly for several quantitative measures that should correlate with different components of the phenotype, rather than using a single composite measure or employing categorical definitions of subtypes. Our measures include the traditional IQ/reading discrepancy score, as well as tests of word recognition, irregular-word reading, and nonword reading. Pointwise analysis by means of sib-pair trait differences suggests the presence, in 6p21.3, of a QTL influencing multiple components of dyslexia, in particular the reading of irregular words (P=.0016) and nonwords (P=.0024). A complementary statistical approach involving estimation of variance components supports these findings (irregular words, P=.007; nonwords, P=.0004). Multipoint analyses place the QTL within the D6S422-D6S291 interval, with a peak around markers D6S276 and D6S105 consistently identified by approaches based on trait differences (irregular words, P=.00035; nonwords, P=.0035) and variance components (irregular words, P=.007; nonwords, P=.0038). Our findings indicate that the QTL affects both phonological and orthographic skills and is not specific to phoneme awareness, as has been previously suggested. Further studies will be necessary to obtain a more precise localization of this QTL, which may lead to the isolation of one of the genes involved in developmental dyslexia.

Adolescent↗
PubMed1999

An optimal algorithm for automatic genotype elimination.

In an effort to accelerate likelihood computations on pedigrees, Lange and Goradia defined a genotype-elimination algorithm that aims to identify those genotypes that need not be considered during the likelihood computation. For pedigrees without loops, they showed that their algorithm was optimal, in the sense that it identified all genotypes that lead to a Mendelian inconsistency. Their algorithm, however, is not optimal for pedigrees with loops, which continue to pose daunting computational challenges. We present here a simple extension of the Lange-Goradia algorithm that we prove is optimal on pedigrees with loops, and we give examples of how our new algorithm can be used to detect genotyping errors. We also introduce a more efficient and faster algorithm for carrying out the fundamental step in the Lange-Goradia algorithm-namely, genotype elimination within a nuclear family. Finally, we improve a common algorithm for computing the likelihood of a pedigree with multiple loops. This algorithm breaks each loop by duplicating a person in that loop and then carrying out a separate likelihood calculation for each vector of possible genotypes of the loop breakers. This algorithm, however, does unnecessary computations when the loop-breaker vector is inconsistent. In this paper we present a new recursive loop breaker-elimination algorithm that solves this problem and illustrate its effectiveness on a pedigree with six loops.

Algorithms↗
PubMed1999

Absence of a relationship between endometriosis and the N314D polymorphism of galactose-1-phosphate uridyl transferase in a UK population.

An association between the N314D polymorphism of galactose-1-phosphate uridyl transferase and endometriosis has recently been reported in a North American population. To determine whether such an association exists in the UK population, we genotyped 148 women with sporadic (n = 91) or familial (n = 57) endometriosis, a control population of 95 male blood donors and a control group of 53 women with a normal pelvis at hysterectomy. Heterozygosity for the polymorphism was found in 14.9% (22/148) of affected women, 13.7% (13/95) of male blood donors and 11.3% (6/53) of women with a normal pelvis. There was no statistically significant difference in the frequency of the polymorphism between cases and controls in the UK population, even when the cases were divided into groups of moderate-severe disease, sporadic cases or familial cases. We conclude that the galactose-1-phosphate uridyl transferase N314D polymorphism is unlikely to be associated with endometriosis in the UK population.

Adult↗
PubMed1999

Discovery of cancer susceptibility genes: study designs, analytic approaches, and trends in technology.

Determining the genetic causes of cancers has immense public health benefits, ranging from prevention to earlier detection and treatment of disease. Although a number of cancer susceptibility genes have been successfully identified, design and analytic issues remain that challenge the current paradigm of gene discovery. Some examples are the definition and measurement of cancer phenotype, the use of intermediate end points, the choice of sample (e.g., affected relative pairs versus large extended pedigrees), the choice of analytic method [e.g., parametric logarithm of the odds (LOD) score method versus model-free methods], and the influence of gene-environment interaction on linkage analysis. Furthermore, association methods, based on either the traditional case-control study design or family-based controls, are popular choices to evaluate candidate genes or screen for linkage disequilibrium. Finally, the study design and analytic methods for gene discovery are determined to some extent by what genomic technology is feasible within the laboratory. Many of the main issues related to gene discovery, as well as trends in genomic technology that will impact on gene discovery, are discussed from the perspective of their strengths and weaknesses, pointing to areas in need of further work.

Genes↗
PubMed1998

A genome-wide screen for susceptibility loci in ankylosing spondylitis.

OBJECTIVE: To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). METHODS: One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. RESULTS: When only the MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. CONCLUSION: The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.

Chromosome Mapping↗
PubMed1998

Molecular genetic investigations of autism.

Genetic factors are likely to play a major role in the etiology of autism. The genetics of the disorder is however complex, probably involving the action of several genes. In an attempt to identify autism susceptibility loci we are currently undertaking a systematic screening of the whole human genome using multiplex families. We describe the resources and the methods needed to achieve such a task, including extensive collection of family data, semiautomated genotyping technology, and specialized statistical approaches for linkage analysis of complex traits.

Autistic Disorder↗
PubMed1998

PedCheck: a program for identification of genotype incompatibilities in linkage analysis.

Prior to performance of linkage analysis, elimination of all Mendelian inconsistencies in the pedigree data is essential. Often, identification of erroneous genotypes by visual inspection can be very difficult and time consuming. In fact, sometimes the errors are not recognized until the stage of running linkage-analysis software. The effort then required to find the erroneous genotypes and to cross-reference pedigree and marker data that may have been recoded and renumbered can be not only tedious but also quite daunting, in the case of very large pedigrees. We have implemented four error-checking algorithms in a new computer program, PedCheck, which will assist researchers in identifying all Mendelian inconsistencies in pedigree data and will provide them with useful and detailed diagnostic information to help resolve the errors. Our program, which uses many of the algorithms implemented in VITESSE, handles large data sets quickly and efficiently, accepts a variety of input formats, and offers various error-checking algorithms that match the subtlety of the pedigree error. These algorithms range from simple parent-offspring-compatibility checks to a single-locus likelihood-based statistic that identifies and ranks the individuals most likely to be in error. We use various real data sets to illustrate the power and effectiveness of our program.

Algorithms↗
PubMed1998

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.

Chromosomes, Human, Pair 12↗
PubMed1998

Autosomal recessive juvenile parkinsonism maps to 6q25.2-q27 in four ethnic groups: detailed genetic mapping of the linked region.

Parkinson disease (PD) is a common neurodegenerative condition associated with degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. There is increasing evidence that genetic factors play a role in the etiology of PD, although genetic heterogeneity is likely. An autosomal dominant syndrome with many similarities to sporadic PD has been mapped to 4q21-22 in a large Italian pedigree and has been found to be due to mutation of the alpha-synuclein gene. However, this gene appears to account for only a minority of PD, and a susceptibility locus for autosomal dominant parkinsonism has recently been mapped, on 2p13. Autosomal recessive juvenile parkinsonism (JP), which shows marked clinical similarity to PD, maps to 6q25.2-q27. We found linkage to this region in a group of 15 families from four distinct ethnic backgrounds. A full genomic screen excluded other candidate regions. We have constructed a detailed genetic map of the linked region and have mapped the position of the manganese superoxide dismutase gene (SOD2). Recombination events restricted the JP locus to a 6.9-cM region and excluded SOD2. The apparent homozygosity for null alleles at D6S955 in one family suggested a deletion and finer localization of the JP locus.

Age of Onset↗
PubMed1998

Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphorylation and multiple mtDNA deletions frequently in skeletal muscle. We studied four ethnically distinct families affected with this apparently autosomal recessive disorder. Probands from each family were shown, by Southern blot, to have multiple mtDNA deletions in skeletal muscle. We mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum two-point LOD score of 6.80 at locus D22S526. Cosegregation of MNGIE with a single chromosomal region in families with diverse ethnic backgrounds suggests that we have mapped an important locus for this disorder. We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase.

Adolescent↗