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N H Chapman

Publications and source records attributed to N H Chapman.

15 recordsLinked to original sources
PubMed2005

A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency.

Dyslexia is a common and complex developmental disorder manifested by unexpected difficulty in learning to read. Multiple different measures are used for diagnosis, and may reflect different biological pathways related to the disorder. Impaired phonological decoding (translation of written words without meaning cues into spoken words) is thought to be a core deficit. We present a genome scan of two continuous measures of phonological decoding ability: phonemic decoding efficiency (PDE) and word attack (WA). PDE measures both accuracy and speed of phonological decoding, whereas WA measures accuracy alone. Multipoint variance component linkage analyses (VC) and Markov chain Monte-Carlo (MCMC) multipoint joint linkage and segregation analyses were performed on 108 families. A strong signal was observed on chromosome 2 for PDE using both VC (LOD=2.65) and MCMC methods (intensity ratio (IR)=32.1). The IR is an estimate of the ratio of the posterior to prior probability of linkage in MCMC analysis. The chromosome 2 signal was not seen for WA. More detailed mapping with additional markers provided statistically significant evidence for linkage of PDE to chromosome 2, with VC-LOD=3.0 and IR=59.6 at D2S1399. Parametric analyses of PDE, using a model obtained by complex segregation analysis, provided a multipoint maximum LOD=2.89. The consistency of results from three analytic approaches provides strong evidence for a locus on chromosome 2 that influences speed but not accuracy of phonological decoding.

Adolescent↗
PubMed2003

A model for the length of tracts of identity by descent in finite random mating populations.

Linkage disequilibrium (LD) reflects coinheritance of an ancestral segment by chromosomes in a population. To begin to understand the effects of population history on the extent of LD, we model the length of a tract of identity-by-descent (IBD) between two chromosomes in a finite, random mating population. The variance of an IBD tract is large: a model described by (Genet. Res. Cambridge 35 (1980) 131) underestimates this variance. Using Fisher's concept of junctions, we predict the mean length of an IBD tract, given the age of the population and the population sizes over time. We derive results also for subdivided populations, given times of subdivision events and sizes of the resulting subpopulations. The model demonstrates that population growth and subdivision strongly affect the expected length of an IBD tract in small populations. These effects are less dramatic in large populations.

Chromosomes↗
PubMed2001

TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam.

BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.

Adult↗
PubMed2001

The importance of connections: joining components of the Hutterite pedigree.

We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub-pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended pedigrees and the FASTLINK package. Markov chain Monte Carlo (MCMC) methods were used to assess haplotype sharing among affected individuals (MORGAN/AUTOZYG), and to perform a combined oligogenic segregation and linkage analysis (LOKI) for log10(IgE). We found evidence for at least two susceptibility loci for asthma on chromosome 5, and a QTL for log10(IgE) on chromosome 1. Our analyses demonstrate that using the most complete pedigree structure possible is advisable, with attention to the possibility of heterogeneity among subunits of a very large pedigree.

Adult↗
PubMed2001

Linkage disequilibrium mapping: the role of population history, size, and structure.

Linkage disequilibrium mapping attempts to infer the location of a disease gene from observed associations between marker alleles and disease phenotype. This approach can be quite powerful when disease chromosomes are descended from a single founder mutation and the markers considered are tightly linked to the disease locus. The success of linkage disequilibrium map ping in fine-scale localization has led to the suggestion that genome-wide association testing might be useful in the detection of susceptibility genes for complex traits. Such studies would likely be performed in small, relatively isolated founder populations, where heterogeneity of the disease is less likely. To interpret the patterns of association observed in such populations, we need to understand the effect of population size, history, and structure on linkage disequilibrium. In this chapter, we first review measures of allelic association at a single locus. Measures of association between two loci are described, and some theoretical results are reviewed. We then consider some methods for inferring linkage between a marker and a rare disease, focusing on those that model the ancestry of the disease chromosomes. Next we discuss factors whose effect on disequilibrium are understood, and finally we describe the characteristics of some human populations that may be useful for disequilibrium mapping of complex traits.

Analysis of Variance↗
PubMed1999

A randomized trial of 72- versus 24-hour intravenous tubing set changes in newborns receiving lipid therapy.

OBJECTIVE: To compare the microbial contamination rate of infusate in the intravenous tubing of newborns receiving lipid therapy, replacing the intravenous delivery system at 72-hour versus 24-hour intervals. DESIGN: Infants requiring intravenous lipid therapy were randomly assigned to have intravenous sets changed on a 72- or a 24-hour schedule, in a 3:1 ratio, in order to compare the infusate contamination rates in an equivalent number of tubing sets. SETTING: A 35-bed, teaching, referral, neonatal intensive-care unit (NICU). PARTICIPANTS: All neonates admitted to the NICU for whom intravenous lipid was ordered. METHODS: Patients were randomized in pharmacy, on receipt of the order for intravenous lipid therapy, to either 72- or 24-hour administration set changes, and followed until 1 week after discontinuation of lipids or discharge from the NICU. Microbial contamination of the infusate was assessed in both groups at the time of administration set changes. Contamination rates were analyzed separately for the lipid and amino acid-glucose tubing sets. Patient charts were reviewed for clinical and epidemiological data, including birth weight, gestational age, gender, age at start of lipid therapy, duration of parenteral nutrition, and type of intravenous access. RESULTS: During the study period, 1,101 and 1,112 sets were sampled in the 72- and 24-hour groups, respectively. Microbial contamination rates were higher in the 72-hour group than the 24-hour group for lipid infusions (39/1,101 [3.54%] vs 15/1,112 [1.35%]; P=.001) and for amino acid infusions (12/1,093 [1.10%] vs 4/1,103 [0.36%]; P=.076). Logistic regression analysis controlling for birth weight, gestational age, and type of venous access showed that only the tubing change interval was significantly associated with lipid set contaminations (odds ratio, 2.69; P=.0013). The rate of blood cultures ordered was higher in the 72- versus the 24-hour group (6.11 vs 4.99 per 100 patient days of total parenteral nutrition; P=.017), and a higher proportion of infants randomized to the 72-hour group died (8% vs 4%; P=.05), although the excess deaths could not clearly be attributed to bacteremia. CONCLUSION: Microbial contamination of infusion sets is significantly more frequent with 72- than with 24-hour set changes in neonates receiving lipid solutions. This may be associated with an increased mortality rate.

Bacteremia↗
PubMed1999

Born to clot: the European burden.

Venous thrombosis is a common problem, predominantly afflicting people of European origin. This European predisposition has been explained to some extent by the recent characterization of factor V Leiden, and the G20210A prothrombin variant. Although it is clear that factor V Leiden is largely confined to Europeans, the world distribution of the prothrombin variant is not known. We have analysed samples from 22 different non-European countries and shown that this prothrombin variant is very rare outside Europe: one case occurring in India. The reason for the confined distribution of these two mutations is unclear.

Africa↗
PubMed1998

Genome screens using linkage disequilibrium tests: optimal marker characteristics and feasibility.

Linkage disequilibrium (LD) testing has become a popular and effective method of fine-scale disease-gene localization. It has been proposed that LD testing could also be used for genome screening, particularly as dense maps of diallelic markers become available and automation allows inexpensive genotyping of diallelic markers. We compare diallelic markers and multiallelic markers in terms of sample sizes required for detection of LD, by use of a single marker locus in a case-control study, for rare monophyletic diseases with Mendelian inheritance. We extrapolate from our results to discuss the feasibility of single-marker LD screening in more-complex situations. We have used a deterministic population genetic model to calculate the expected power to detect LD as a function of marker density, age of mutation, number of marker alleles, mode of inheritance of a rare disease, and sample size. Our calculations show that multiallelic markers always have more power to detect LD than do diallelic markers (under otherwise equivalent conditions) and that the ratio of the number of diallelic to the number of multiallelic markers needed for equivalent power increases with mutation age and complexity of mode of inheritance. Power equivalent to that achieved by a multiallelic screen can theoretically be achieved by use of a more dense diallelic screen, but mapping panels of the necessary resolution are not currently available and may be difficult to achieve. Genome screening that uses single-marker LD testing may therefore be feasible only for young (<20 generations), rare, monophyletic Mendelian diseases, such as may be found in rapidly growing genetic isolates.

Alleles↗
PubMed1997

Segregation and linkage analysis of a quantitative versus a qualitative trait in large pedigrees.

Goals of this analysis were to map loci contributing to variation in the quantitative trait, Q1, using the lod-score method on data set 1, and to explore the difference in power to map genes when considering the discrete vs. quantitative phenotype. Segregation analyses, after covariate adjustment, correctly suggested two contributing loci. The major gene on chromosome 5 was successfully mapped, but the major gene on chromosome 8 was not. Comparison of linkage analyses for the qualitative and quantitative traits confirmed that the quantitative trait is more informative, suggesting that localizing disease genes with a qualitative trait would be more difficult in these pedigrees.

Chromosome Mapping↗
PubMed1997

Global distribution of the CCR5 gene 32-basepair deletion.

A mutant allele of the beta-chemokine receptor gene CCR5 bearing a 32-basepair (bp) deletion (denoted delta ccr5) which prevents cell invasion by the primary transmitting strain of HIV-1 has recently been characterized. Homozygotes for the mutation are resistant to infection, even after repeated high-risk exposures, but this resistance appears not to be total, as isolated cases of HIV-positive deletion homozygotes are now emerging. The consequence of the heterozygous state is not clear, but it may delay the progression to AIDS in infected individuals. A gene frequency of approximately 10% was found for delta ccr5 in populations of European descent, but no mutant alleles were reported in indigenous non-European populations. As the total number of non-European samples surveyed was small in comparison with the Europeans the global distribution of this mutation is far from clear. We have devised a rapid PCR assay for delta ccr5 and used it to screen 3,342 individuals from a globally-distributed range of populations. We find that delta ccr5 is not confined to people of European descent but is found at frequencies of 2-5% throughout Europe, the Middle East and the Indian subcontinent (Fig. 1). Isolated occurrences are seen elsewhere throughout the world, but these most likely represent recent European gene flow into the indigenous populations. The inter-population differences in delta ccr5 frequency may influence the pattern of HIV transmission and so will need to be incorporated into future predictions of HIV levels.

Africa↗
PubMed1996

Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans.

Lp[a] concentrations in nmol/L and apo[a] size isoforms, expressed in terms of the relative number of apo[a] kringle 4 (K4) repeats, were determined in 3959 whites and blacks from four U.S. communities. Plasma Lp[a] analyses were performed by an ELISA method insensitive to apo[a] size heterogeneity and apo[a] size isoforms were determined by high resolution agarose gel electrophoresis. Allele frequencies were estimated by maximum likelihood methods in order to account for the presence of null alleles and coalescence of hands on gels. The apo[a] allele frequencies and phenotype distributions differed significantly between blacks and whites (P < 0.0001). Blacks had a higher relative frequency of the intermediate alleles K4(22) through K4(28) whereas whites had a higher relative frequency of the small alleles K4(17) through K4(24) and large alleles K4(29) through K4(33). The estimated frequency of the null allele was low in both blacks (1.0%) and whites (6.7%). The Lp[a] distribution was less skewed and Lp[a] concentrations were higher in blacks than whites (mean 94 nmol/L and 48 nmol/L, median 74 nmol/L and 20 nmol/L for blacks and whites, respectively). The relationship between apo[a] size and Lp[a] concentration also differed significantly between these two racial groups. For the large polymorphs (> 31 K4 repeats) both blacks and whites exhibited uniformly low Lp[a] values. For the intermediate isoforms K4(20) through K4(30), a considerable range of Lp[a] values was evident in blacks; the median Lp[a] for each isoform increased nearly linearly as the apo[a] size decreased. In contrast in whites there was little change in median Lp[a] concentrations for isoforms K4(20) through K4(30). For the small apo[a] size (< 20 K4) both blacks and whites exhibited high median Lp[a] levels and a wide variation of Lp[a] levels. The major difference in Lp[a] levels between the two racial groups occurred in the intermediate size isoform range of K4(20) through K4(25). In conclusion, whites and blacks differ significantly in Lp[a] concentrations, allele and phenotype frequencies, and in the relationship between apo[a] size isoform and Lp[a] concentration.

Adolescent↗
PubMed1995

Evaluation of genetic and environmental effects using GEE and APM methods.

Two analytic methods were used in the Problem 2 data set. First, generalized estimating equations (GEE) modelling was developed to adjust for familial correlation in regressions evaluating candidate genes and an environmental factor. Second, the affected-pedigree-member (APM) method was used to identify chromosomal regions of interest and linkage of candidate genes with disease affection status. The GEE method identified C5 (MG1) as important for the quantitative trait Q1 and the corresponding affection status DIS, but the APM method was only suggestive. The GEE method identified C2 (MG2) as important for Q2 but only marginally important for Q1 and not important for DIS.

Data Interpretation, Statistical↗
PubMedDate not supplied

Linkage of hereditary distal myopathy with desmin accumulation to 2q.

We are investigating the genetics of a large family with an autosomal dominant form of hereditary distal myopathy. This slowly progressive myopathy begins during early adulthood in the distal leg muscles, producing a gait disturbance. Cardiomyopathy is also present in most affected family members, manifesting itself as conduction block or congestive heart failure. Histologically, an accumulation of the protein, desmin, occurs in the subsarcolemmal spaces of myofibers. We have performed linkage analyses of this family, and have mapped the location of the gene causing the myopathy to human chromosome 2q33. The gene is within a 17-cM segment of chromosome 2q bounded by the DNA markers D2S2248 and D2S401. The best candidate gene for this myopathy is desmin.

Chromosome Mapping↗