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Biomedical subjects

Robert C Elston

Publications and source records attributed to Robert C Elston.

At least 19 recordsLinked to original sources
PubMed2003

Heritability analysis of cytokines as intermediate phenotypes of tuberculosis.

Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-alpha, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-gamma, TNF-alpha, and TGF-beta reflected the immunologic model of TB. In this analysis, the first component explained >38% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.

Adolescent↗
PubMed2003

The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity.

There is currently a great deal of interest in using linkage disequilibrium (LD) mapping to locate both disease and quantitative-trait loci on a genomewide scale. Recent findings suggest that much of the human genome is organized in discrete "blocks" of low haplotype diversity, but the utility of such blocks in identifying genes influencing complex traits is not yet known and must ultimately be tested empirically through use of real data. We recently identified a putative functional polymorphism (-1021C-->T) in the 5' upstream region of the DBH gene that accounted for 35%-52% of the total phenotypic variance in plasma dopamine beta-hydroxylase (DBH) activity in samples from three distinct populations. In the present study, we genotyped 11 diallelic markers at the DBH locus surrounding -1021C-->T in 386 unrelated individuals of European origin. We identified a single 10-kb block containing -1021C-->T, in which four haplotypes comprised 93% of the observed chromosomes. Only markers within the block were highly associated with phenotype (P< or =2.2 x 10(-10)), with one exception. In general, association with phenotype was strongly correlated with the degree of LD between each marker and -1021C-->T. Of four LD measures assessed, d(2) was the best predictor of this relationship. Had one attempted to map quantitative-trait loci for plasma DBH activity on a genomewide basis without prior knowledge of candidate regions and not included (by chance) markers within this haplotype block, the DBH locus might have been missed entirely. These results provide a direct example of the potential value of constructing a haplotype map of the human genome prior to embarking on large-scale association studies.

Adult↗
PubMed2003

A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.

Adult↗
PubMed2003

New multivariate test for linkage, with application to pleiotropy: fuzzy Haseman-Elston.

We propose a new method of linkage analysis based on using the grade of membership scores resulting from fuzzy clustering procedures to define new dependent variables for the various Haseman-Elston approaches. For a single continuous trait with low heritability, the aim was to identify subgroups such that the grade of membership scores to these subgroups would provide more information for linkage than the original trait. For a multivariate trait, the goal was to provide a means of data reduction and data mining. Simulation studies using continuous traits with relatively low heritability (H=0.1, 0.2, and 0.3) showed that the new approach does not enhance power for a single trait. However, for a multivariate continuous trait (with three components), it is more powerful than the principal component method and more powerful than the joint linkage test proposed by Mangin et al. ([1998] Biometrics 54:88-99) when there is pleiotropy.

Cluster Analysis↗
PubMed2003

Optimal two-stage genotyping in population-based association studies.

We propose a cost-effective two-stage approach to investigate gene-disease associations when testing a large number of candidate markers using a case-control design. Under this approach, all the markers are genotyped and tested at stage 1 using a subset of affected cases and unaffected controls, and the most promising markers are genotyped on the remaining individuals and tested using all the individuals at stage 2. The sample size at stage 1 is chosen such that the power to detect the true markers of association is 1-beta(1) at significance level alpha(1). The most promising markers are tested at significance level alpha(2) at stage 2. In contrast, a one-stage approach would evaluate and test all the markers on all the cases and controls to identify the markers significantly associated with the disease. The goal is to determine the two-stage parameters (alpha(1), beta(1), alpha(2)) that minimize the cost of the study such that the desired overall significance is alpha and the desired power is close to 1-beta, the power of the one-stage approach. We provide analytic formulae to estimate the two-stage parameters. The properties of the two-stage approach are evaluated under various parametric configurations and compared with those of the corresponding one-stage approach. The optimal two-stage procedure does not depend on the signal of the markers associated with the study. Further, when there is a large number of markers, the optimal procedure is not substantially influenced by the total number of markers associated with the disease. The results show that, compared to a one-stage approach, a two-stage procedure typically halves the cost of the study.

Case-Control Studies↗
PubMed2003

Familial correlations and heritability of maxillary midline diastema.

The purpose of the study was to estimate familial correlations and heritability to evaluate familial aggregation patterns of maxillary midline diastemas. The sample consisted of 30 extended families: 15 black, 14 white, and 1 mixed race. A single ascertainment scheme was adopted to collect the sample. Family data were collected with a 7-question survey. In all, the sample of 430 subjects consisted of 220 females, 210 males, 99 nuclear families, 534 sibling pairs, 422 avuncular pairs, 318 grandparent pairs, and 27 cousin pairs. Families were stratified by race to avoid any bias. The mixed-race family was excluded from the analysis. Data were analyzed using the program REGC in the Statistical Analysis for Genetic Epidemiology (S.A.G.E., Case Western Reserve University, Cleveland, Ohio) software. Heritability was found to be 0.32 +/- 0.14 in the white sample and 0.04 +/- 0.16 in the black sample. The preliminary results suggest a possible genetic basis for maxillary midline diastema and a greater role of environmental factors in the black sample than in the white sample.

Adolescent↗
PubMed2003

Nonparametric disequilibrium mapping of functional sites using haplotypes of multiple tightly linked single-nucleotide polymorphism markers.

As the speed and efficiency of genotyping single-nucleotide polymorphisms (SNPs) increase, using the SNP map, it becomes possible to evaluate the extent to which a common haplotype contributes to the risk of disease. In this study we propose a new procedure for mapping functional sites or regions of a candidate gene of interest using multiple linked SNPs. Based on a case-parent trio family design, we use expectation-maximization (EM) algorithm-derived haplotype frequency estimates of multiple tightly linked SNPs from both unambiguous and ambiguous families to construct a contingency statistic S for linkage disequilibrium (LD) analysis. In the procedure, a moving-window scan for functional SNP sites or regions can cover an unlimited number of loci except for the limitation of computer storage. Within a window, all possible widths of haplotypes are utilized to find the maximum statistic S* for each site (or locus). Furthermore, this method can be applied to regional or genome-wide scanning for determining linkage disequilibrium using SNPs. The sensitivity of the proposed procedure was examined on the simulated data set from the Genetic Analysis Workshop (GAW) 12. Compared with the conventional and generalized TDT methods, our procedure is more flexible and powerful.

Algorithms↗
PubMed2003

Adding further power to the Haseman and Elston method for detecting linkage in larger sibships: weighting sums and differences.

Haseman and Elston (H-E) proposed a robust test to detect linkage between a quantitative trait and a genetic marker. In their method the squared sib-pair trait difference is regressed on the estimated proportion of alleles at a locus shared identical by descent by sib pairs. This method has recently been improved by changing the dependent variable from the squared difference to the mean-corrected product of the sib-pair trait values, a significantly positive regression indicating linkage. Because situations arise in which the original test is more powerful, a further improvement of the H-E method occurs when the dependent variable is changed to a weighted average of the squared sib-pair trait difference and the squared sib-pair mean-corrected trait sum. Here we propose an optimal method of performing this weighting for larger sibships, allowing for the correlation between pairs within a sibship. The optimal weights are inversely proportional to the residual variances obtained from the two different regressions based on the squared sib-pair trait differences and the squared sib-pair mean-corrected trait sums, respectively, allowing for correlations among sib pairs. The proposed method is compared with the existing extension of the H-E approach for larger sibships. Control of the type I error probabilities for sibships of any size can be improved by using a generalized estimating equation approach and the robust sandwich estimate of the variance, or a Monte-Carlo permutation test.

Computer Simulation↗
PubMed2003

Regression models for linkage: issues of traits, covariates, heterogeneity, and interaction.

Regression methods offer a common framework to analyze linkage for quantitative trait loci as well as linkage for affection status using affected sib-pairs. Although numerous papers on regression methods for linkage have been published, some common themes and important caveats tend to be scattered across the literature. For example, the typical approach is to regress a function of traits on identical-by-descent (IBD) information, but the reversal (regression of IBD on a function of traits) offers important insights. A second example is the use of regression equations to assess linkage heterogeneity or gene-environment interaction, and why these two different etiologies are difficult to distinguish with affected sib-pair data. A third example has to do with the differences, and similarities, between linear regression and non-linear regression methods for affected sib-pair data. The purposes of this paper are to review some recent developments in the linkage regression framework, to emphasize strengths and weaknesses of various proposed methods, and to highlight some important assumptions and caveats.

Data Interpretation, Statistical↗
PubMed2003

X-linked extension of the revised Haseman-Elston algorithm for linkage analysis in sib pairs.

Haseman and Elston (H-E) proposed a regression-based robust test of linkage between a marker and an autosomal quantitative trait locus, using the squared sib pair trait difference as a dependent variable and the proportion of alleles shared identical by descent by the sib pair as an independent variable. Several authors have proposed improvement of the original H-E's seminal work by using an optimal linear combination of squared sum and squared difference as the dependent variable. In this paper, we extend Haseman and Elston's sib pair method to an X-linked locus. We give a general formulation of the complete regression model and details of the regression coefficients in terms of variance components. Simulation results are presented to describe the power of this technique for a theoretical best case scenario.

Algorithms↗
PubMed2002

A whole-genome scan for obstructive sleep apnea and obesity.

Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n=349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels.

Adult↗
PubMed2002

Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis.

Differences in age of presentation and anatomic risk factors for obstructive sleep apnea (OSA) in Caucasians and African Americans suggest possible racial differences in the genetic underpinnings of the disorder. In this study, we assess transmission patterns in a Caucasian sample consisting of 177 families (N = 1,195) and in an African American sample consisting of 125 families (N = 720) for two variables: 1) apnea hypopnea index (AHI) log transformed and adjusted for age, and 2) AHI log transformed and adjusted for age and body mass index (BMI). We allowed for residual familial correlations and sex-specific means in all models. Analysis of the Caucasian sample showed transmission patterns consistent with that of a major gene that were stronger in the age-adjusted variable than in the age- and BMI-adjusted variable. However, in the African American families, adjusting for BMI in addition to age gave stronger evidence for segregation of a codominant gene with an allele frequency of 0.14, accounting for 35% of the total variance. These results provide support for an underlying genetic basis for OSA that in African Americans is independent of the contribution of BMI.

Black or African American↗
PubMed2002

Increase in power of transmission-disequilibrium tests for quantitative traits.

Allison ([1997] Am. J. Hum. Genet. 60:676-690) proposed four versions of the transmission-disequilibrium test (TDT) for quantitative traits when there is extreme-threshold sampling, i.e., the trios having an offspring trait value between a priori defined thresholds are excluded from the analysis. Keeping intact the ideology and construction of these tests, we propose here an extreme-offspring design for the trios: for each parent pair of which at least one is heterozygous at a marker locus, the offspring having the most extreme trait value is selected for the trio. Our simulation studies show that the effect of the extreme-offspring design can be quite substantial (up to 30% increase in test power), and that the increase is greater for smaller values of the association parameter and for traits with smaller heritability: just those cases where the increase in power is especially desirable.

Data Interpretation, Statistical↗
PubMed2002

Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes.

Genetic studies suggest a diabetes susceptibility locus on human chromosome 20, near the melanocortin receptor-3 (MC3-R) gene. We examined the MC3-R as a candidate gene for type 2 diabetes in 12 members of a large Maori kindred with multiple affected members. The coding region of the MC3-R gene was sequenced for both diabetic and non-diabetic individuals. Two separate single base pair substitutions were found in the MC3-R coding sequence and these resulted in amino acid changes, Lysine6Threonine and Isoleucine81Valine. Neither of these MC3-R variants tracked with the presence of diabetes. Furthermore, the variant and wild type MC3-R showed similar functional coupling to adenylyl cyclase. A polymorphic marker (D20S32e) close to the human MC3-R (hMC3-R) coding sequence was investigated in a 60-member pedigree for association with diabetes and other metabolic parameters. There was an association between D20S32e genotype and fasting insulin (P=0.0085) and the insulin resistance index, HOMA-R (P=0.0042). An association was also found between genotype and HDL levels during oral glucose tolerance testing (P=0.0037). These associations were independent of BMI, age, gender and diabetes. Our data do not support a role for variations in the coding region of the hMC3-R in the development of type 2 diabetes in this Maori kindred, but suggest that a locus on chromosome 20 q, close to D20S32e, may contribute to both insulin secretion and action in the Maori kindred.

Age of Onset↗
PubMed2002

Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro.

Human immunodeficiency virus type 1 (HIV-1) Gag protease cleavage sites (CS) undergo sequence changes during the development of resistance to several protease inhibitors (PIs). We have analyzed the association of sequence variation at the p7/p1 and p1/p6 CS in conjunction with amprenavir (APV)-specific protease mutations following PI combination therapy with APV. Querying a central resistance data repository resulted in the detection of significant associations (P < 0.001) between the presence of APV protease signature mutations and Gag L449F (p1/p6 LP1'F) and P453L (p1/p6 PP5'L) CS changes. In population-based sequence analyses the I50V mutant was invariably linked to either L449F or P453L. Clonal analysis revealed that both CS mutations were never present in the same genome. Sequential plasma samples from one patient revealed a transition from I50V M46L P453L viruses at early time points to I50V M46I L449F viruses in later samples. Various combinations of the protease and Gag mutations were introduced into the HXB2 laboratory strain of HIV-1. In both single- and multiple-cycle assay systems and in the context of I50V, the L449F and P453L changes consistently increased the 50% inhibitory concentration of APV, while the CS changes alone had no measurable effect on inhibitor sensitivity. The decreased in vitro fitness of the I50V mutant was only partially improved by addition of either CS change (I50V M46I L449F mutant replicative capacity approximately 16% of that of wild-type virus). Western blot analysis of Pr55 Gag precursor cleavage products from infected-cell cultures indicated accumulation of uncleaved Gag p1-p6 in all I50V viruses without coexisting CS changes. Purified I50V protease catalyzed cleavage of decapeptides incorporating the L449F or P453L change 10-fold and 22-fold more efficiently than cleavage of the wild-type substrate, respectively. HIV-1 protease CS changes are selected during PI therapy and can have effects on both viral fitness and phenotypic resistance to PIs.

Binding Sites↗
PubMed2002

The linkage information content value of polymorphism genetic markers in model-free linkage analysis.

Guo and Elston [Hum Hered 1999;49:112-118] developed a linkage information content (LIC) value to measure the informativeness of a marker for identity-by-descent (IBD) sharing status of relative pairs. LIC values were derived for five types of relative pairs: full sib, half sib, grandparent-grandchild, first cousin and avuncular. In this paper, we give corrected LIC values for full sib, grandparent-grandchild, first cousin and avuncular pairs, and indicate the availability of a computer program to calculate them.

Chromosome Mapping↗