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Biomedical subjects

E M Wijsman

Publications and source records attributed to E M Wijsman.

At least 19 recordsLinked to original sources
PubMed2006

Evidence for multiple loci from a genome scan of autism kindreds.

We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P=0.0006, 133.16 cM) on chromosome 7q at a location coincident with other linkage studies. When a more relaxed diagnostic criteria was used, linkage evidence at this location was weaker (P=0.01). The sample was stratified into families with only male affected subjects (MO) and families with at least one female affected subject (FC). The strongest signal unique to the MO group was on chromosome 11 (P=0.0009, 83.82 cM), and for the FC group on chromosome 4 (P=0.002, 111.41 cM). We also divided the sample into regression positive and regression negative families. The regression-positive group showed modest linkage signals on chromosomes 10 (P=0.003, 0 cM) and 14 (P=0.005, 104.2 cM). More significant peaks were seen in the regression negative group on chromosomes 3 (P=0.0002, 140.06 cM) and 4 (P=0.0005, 111.41 cM). Finally, we used language acquisition data as a quantitative trait in our linkage analysis and observed a chromosome 9 signal (149.01 cM) of P=0.00006 and an empirical P-value of 0.0008 at the same location. Our work provides strong conformation for an autism locus on 7q and suggestive evidence for several other chromosomal locations. Diagnostic specificity and detailed analysis of the autism phenotype is critical for identifying autism loci.

Adolescent↗
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

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q.

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Adolescent↗
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

On estimating the proportion of variance in a phenotypic trait attributable to a measured locus.

The measured genotype approach can be used to estimate the variance contributions of specific candidate loci to quantitative traits of interest. We show here that both the naive estimate of measured-locus heritability, obtained by invoking infinite-sample theory, and an estimate obtained from a bias-corrected variance estimate based on finite-sample theory, produce biased estimates of heritability. We identify the sources of bias, and quantify their effects. The two sources of bias are: (1) the estimation of heritability from population samples as the ratio of two variances, and (2) the existence of sampling error. We show that neither heritability estimator is less biased (in absolute value) than the other in all situations, and the choice of an ideal estimator is therefore a function of the sample size and magnitude of the locus-specific contribution to the overall phenotypic variance. In most cases the bias is small, so that the practical implications of using either estimator are expected to be minimal.

Bias↗
PubMed2000

Segregation analysis of phenotypic components of learning disabilities. I. Nonword memory and digit span.

Dyslexia is a common and complex disorder with evidence for a genetic component. Multiple loci (i.e., quantitative-trait loci [QTLs]) are likely to be involved, but the number is unknown. Diagnosis is complicated by the lack of a standard protocol, and many diagnostic measures have been proposed as understanding of the component processes has evolved. One or more genes may, in turn, influence these measures. To date, little work has been done to evaluate the mode of inheritance of individual component-as opposed to composite-phenotypes, beyond family or twin correlation studies that initially demonstrate evidence for a genetic basis of such components. Here we use two approaches to segregation analysis in 102 nuclear families to estimate genetic models for component phenotypes associated with dyslexia: digit span and a nonword-repetition task. Both measures are related to phonological skills, one of the key component processes in dyslexia. We use oligogenic-trait segregation analysis to estimate the number of QTLs contributing to each phenotype, and we use complex segregation analysis to identify the most parsimonious inheritance models. We provide evidence in support of both a major-gene mode of inheritance for the nonword-repetition task, with approximately 2.4 contributing QTLs, and for a genetic basis of digit span, with approximately 1.9 contributing QTLs. Results obtained by reciprocal adjustment of measures suggest that genes contributing to digit span may contribute to the nonword-repetition score but that there are additional QTLs involved in nonword repetition. Our study adds to existing studies of the genetic basis of composite phenotypes related to dyslexia, by providing evidence for major-gene modes of inheritance of these single-measure component phenotypes.

Age Factors↗
PubMed2000

Bias in multipoint linkage analysis arising from map misspecification.

Multipoint linkage analysis methods are often used in human genetic studies. Although multipoint methods increase power for a linkage analysis and will become essential if use of diallelic markers becomes widespread, the methods in use assume an accurate meiotic marker map. Unfortunately, uncertainties in estimates of between-marker meiotic distances are large. Also, sex-averaged maps are generally used, but recombination rates differ in males and females. Both these types of map misspecification can lead to lod score bias, but such bias has not previously been systematically quantified. We examine multipoint lod score bias arising from these map misspecifications, in both the presence and absence of actual linkage. We define bias as the expected difference between the lod score computed under the misspecified map and that computed under the true map. With actual linkage, any map misspecification causes negative bias in lod scores, resulting in loss of power to detect linkage. In most cases, bias is modest, only reaching clearly detectable levels when both types of misspecification are substantial. In the absence of linkage, map misspecification can cause positive or negative bias: falsely assuming a 1:1 female:male ratio always causes positive bias; using too large a distance gives a positive bias; using too small a distance gives a negative bias. This bias can inflate the false-positive rate, especially when the sample size is modest. We conclude that although current sex-averaged maps are suitable for a first-pass multipoint screen, the potential for bias from map misspecification should be evaluated in following up results from such an analysis.

Bias↗
PubMed2000

Familial aggregation of dyslexia phenotypes.

There is evidence for genetic contributions to reading disability, but the phenotypic heterogeneity associated with the clinical diagnosis may make identification of the underlying genetic basis difficult. In order to elucidate distinct phenotypic features that may be contributing to the genotypic heterogeneity, we assessed the familial aggregation patterns of Verbal IQ and 24 phenotypic measures associated with dyslexia in 102 nuclear families ascertained through probands in grades 1 through 6 who met the criteria for this disorder. Correlations between relatives were computed for all diagnostic phenotypes, using a generalized estimating equation (GEE) approach. GEE is a recently developed semiparametric method for handling correlated data. The method is robust to model misspecification and flexible in adjusting for the subjects' characteristics and pedigree sizes as well as for the ascertainment process, while estimating the correlations between related subjects. The Nonword Memory (NWM) subtest of a prepublication version of the Comprehensive Test of Phonological Processing (CTOPP) and Phonemic Decoding Efficiency (PDE) subtest of a prepublication version of the Test of Word Reading Efficiency (TOWRE) showed correlation patterns in relatives that are strongly supportive of a genetic basis. The Wechsler Scale Digit Span, the Word Attack subtest of the Woodcock Reading Mastery Test--Revised, and the Spelling subtest of the Wide Range Achievement Test--Third Edition had slightly weaker evidence of a genetic basis. Five additional phenotypes (the Spelling subtest of the Wechsler Individual Achievement Test, the Accuracy, Rate, and Comprehension subtests of the Gray Oral Reading Test--Third Edition, and Rapid Automatized Naming of Letters and Numbers) gave suggestive evidence of such a pattern. The results cross-validate in that evidence for a pattern consistent with a genetic basis was obtained for two measures of phonological short-term memory (CTOPP Nonword Memory and WISCIII or WAIS-R Digit Span), for two measures of phonological decoding (WRMT-R Word Attack and TOWRE Phonemic Decoding Efficiency), and for two measures of spelling from dictation (WRAT-3 Spelling and, to a lesser extent, WIAT Spelling). These measures are thus good candidates for more sophisticated segregation analyses that can formulate models for incorporation into linkage analyses.

Adult↗
PubMed2000

The number of trait loci in late-onset Alzheimer disease.

Although it is clear that apoE plays an important role in the genetics of late-onset Alzheimer disease (AD), evidence exists that additional genes may play a role in AD, and estimates of the total contribution of apoE to the variance in onset of AD vary widely. Unfortunately, little information is available on the number and contribution of additional genes. We estimated the number of additional quantitative-trait loci and their contribution to the variance in age at onset of AD, as well as the contribution of apoE and sex, in an oligogenic segregation analysis of 75 families (742 individuals) ascertained for members with late-onset AD. We found evidence that four additional loci make a contribution to the variance in age at onset of late-onset AD that is similar to or greater in magnitude than that made by apoE, with one locus making a contribution several times greater than that of apoE. Additionally, we confirmed previous findings of a dose effect for the apoE varepsilon4 allele, a protective effect for the varepsilon2 allele, evidence for allelic interactions at the apoE locus, and a small protective effect for males. Furthermore, although we estimate that the apoE genotype can make a difference of </=17 years in age at onset of AD, our estimate of the contribution of apoE (7%-9%) to total variation in onset of AD is somewhat smaller than that which has previously been reported. Our results suggest that several genes that have not yet been localized may play a larger role than does apoE in late-onset AD.

Adult↗
PubMed1999

Monte Carlo Markov chain methods for genome screening.

We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait, MAO level, and a discrete trait, Collaborative Study on the Genetics of Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were analyzed and effects of marker map features were examined. For MAO, modest signals were found on chromosomes 1 and 17 for raw data, and 15 for covariate-adjusted data. For alcoholism, a strong signal was found on chromosome 1 with modest signals on chromosomes 4 and 10.

Alcoholism↗
PubMed1999

Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency.

Small low-density lipoprotein (LDL) particles are a genetically influenced coronary disease risk factor. Lipoprotein lipase (LpL) is a rate-limiting enzyme in the formation of LDL particles. The current study examined genetic linkage of LDL particle size to the LpL gene in five families with structural mutations in the LpL gene. LDL particle size was smaller among the heterozygous subjects, compared with controls. Among heterozygous subjects, 44% were classified as affected by LDL subclass phenotype B, compared with 8% of normal family members. Plasma triglyceride levels were significantly higher, and high-density lipoprotein cholesterol (HDL-C) levels were lower, in heterozygous subjects, compared with normal subjects, after age and sex adjustment. A highly significant LOD score of 6.24 at straight theta=0 was obtained for linkage of LDL particle size to the LpL gene, after adjustment of LDL particle size for within-genotype variance resulting from triglyceride and HDL-C. Failure to adjust for this variance led to only a modest positive LOD score of 1.54 at straight theta=0. Classifying small LDL particles as a qualitative trait (LDL subclass phenotype B) provided only suggestive evidence for linkage to the LpL gene (LOD=1. 65 at straight theta=0). Thus, use of the quantitative trait adjusted for within-genotype variance, resulting from physiologic covariates, was crucial for detection of significant evidence of linkage in this study. These results indicate that heterozygous LpL deficiency may be one cause of small LDL particles and may provide a potential mechanism for the increase in coronary disease seen in heterozygous LpL deficiency. This study also demonstrates a successful strategy of genotypic specific adjustment of complex traits in mapping a quantitative trait locus.

Adolescent↗
PubMed1999

Multipoint oligogenic analysis of age-at-onset data with applications to Alzheimer disease pedigrees.

It is usually difficult to localize genes that cause diseases with late ages at onset. These diseases frequently exhibit complex modes of inheritance, and only recent generations are available to be genotyped and phenotyped. In this situation, multipoint analysis using traditional exact linkage analysis methods, with many markers and full pedigree information, is a computationally intractable problem. Fortunately, Monte Carlo Markov chain sampling provides a tool to address this issue. By treating age at onset as a right-censored quantitative trait, we expand the methods used by Heath (1997) and illustrate them using an Alzheimer disease (AD) data set. This approach estimates the number, sizes, allele frequencies, and positions of quantitative trait loci (QTLs). In this simultaneous multipoint linkage and segregation analysis method, the QTLs are assumed to be diallelic and to interact additively. In the AD data set, we were able to localize correctly, quickly, and accurately two known genes, despite the existence of substantial genetic heterogeneity, thus demonstrating the great promise of these methods for the dissection of late-onset oligogenic diseases.

Age Factors↗
PubMed1999

A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation.

In some myopathies of distal onset, the intermediate filament desmin is abnormally accumulated in skeletal and cardiac muscle. We report the first point mutation in desmin cosegregating with an autosomal dominant form of desmin-related myopathy. The L345P desmin missense mutation occurs in a large, six generation Ashkenazi Jewish family. The mutation is located in an evolutionarily highly conserved position of the desmin coiled-coil rod domain important for dimer formation. L345P desmin is incapable of forming filamentous networks in transfected HeLa and SW13 cells. We conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.

Amino Acid Sequence↗
PubMed1998

Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by growth of benign bone tumors. Three chromosomal loci have been implicated in this genetically heterogeneous disease: EXT1 at 8q24, EXT2 at 11p13, and EXT3 on 19p. EXT1 and EXT2 were recently cloned. We evaluated 34 families with EXT to estimate the proportion of disease attributable to EXT1, EXT2, and EXT3 and to investigate the spectrum of EXT1 mutations. Linkage analyses combined with heterogeneity testing provides strong evidence in favor of linkage of disease to both chromosomes 8 and 11, but does not support evidence of linkage to chromosome 19 in this data set. The 11 EXT1 exons were PCR-amplified and sequenced in all 11 isolated cases and in 20 of the 23 familial cases. Twelve different novel EXT1 mutations were detected, including 5 frame-shift deletions or insertions, 1 codon deletion, and 6 single base-pair substitutions distributed across 8 of the exons. Only 2 of the mutations were detected in more than one family. Three mutations affect sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. These residues may be crucial to the function of this protein. Although the prevalence of EXT has been estimated to be approximately 1/50,000 individuals, the disease has been reported to occur much more frequently in the Chamorro natives on Guam. Our detection of an EXT1 mutation in one Chamorro subject will allow investigation of a possible founder effect in this population. Combined mutational and heterogeneity analyses in this set of families with multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnormalities in EXT1.

Chromosomes, Human, Pair 11↗
PubMed1998

Semiparametric estimation of major gene effects for age of onset.

Analysis of age of onset is a key factor in the segregation and linkage analysis of some complex genetic traits. Previous work in the genetics literature has used parametric distributional assumptions on age of onset. In this paper, a Cox model with latent major gene effects is used: a semiparametric model with unspecified baseline hazard. A Monte Carlo EM procedure is used to obtain maximum likelihood estimates. Markov chain Monte Carlo is used to realize genotypic configurations from the posterior distribution given the current model and the observed data, and these genotypic configurations are used to estimate the expectations in the EM algorithm. Simulated data sets indicate that the parameters can be estimated well, and one real data set shows the practical applicability of the proposed method.

Age Distribution↗
PubMed1998

Pedigree analysis package (PAP) vs. MORGAN: model selection and hypothesis testing on a large pedigree.

The MORGAN package of programs is compared to a commonly used package, PAP, with respect to model selection in segregation analysis of a quantitative trait. MORGAN uses Monte Carlo Markov chain (MCMC) methods to estimate the likelihood, whereas both versions of PAP used employ an approximation to the likelihood for the mixed model. Comparisons are done by using results obtained from simulated data. All simulations were done on the same 232-member pedigree using data generated under each of several variations of models, which included different combinations of environmental, polygenic, and major gene components. PAP, version 4.0, and MORGAN gave similar results with respect to model selection for the majority of situations, suggesting that MCMC methods provide a computationally tractable approach for analysis of more complex models that cannot be analyzed by more direct computational methods. PAP, version 3.0, gave somewhat more disparate results compared with either PAP version 4.0 or MORGAN. Both MORGAN and the two versions of PAP confirmed that the major gene component is much easier to detect in the presence of some dominance. All three packages frequently falsely accepted the polygenic model when there was high residual heritability.

Computer Simulation↗