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R C Elston

Publications and source records attributed to R C Elston.

At least 73 records · Page 4Linked to original sources
PubMed1999

Linkage of chromosome 1 markers to alcoholism-related phenotypes by sib pair linkage analysis of principal components.

Using the Collaborative Study on the Genetics of Alcoholism data and affected-sib-pair linkage methods, Reich et al. [1998] reported linkage of alcohol dependence to a region near D1S1588 on chromosome 1. In this paper, we assessed the ability of multivariate sib-pair linkage analysis of the neurophysiologic measurements (including age and sex) to evaluate evidence for linkage to chromosome 1. Principal components of 16 neurophysiologic measurements, plus age and sex, were analyzed separately using sib-pair linkage analysis, and a cumulative sum of the resulting t2-statistics computed at each point on the chromosome. The first four principal components, which accounted for 74% of the total variation, showed little or no evidence for linkage in the D1S1588 region, while the remaining components showed substantial evidence for linkage. We conclude that potentially important linkage results can be missed if investigators limit attention only to major sources of variability.

Age Factors↗
PubMed1999

Association and linkage analysis of ICD-10 diagnosis for alcoholism.

We analyzed the GAW11 data on alcoholism provided by the Collaborative Study on the Genetics of Alcoholism (COGA) using an extension of a new test of linkage and association for quantitative traits developed by George et al. [1999]. This method determines linkage between marker loci and quantitative traits, when allelic association is present between the trait and marker loci, by regressing the disease trait on the parental transmission of the allele of interest. We found no strong evidence of linkage to any markers. However, we found several markers suggestive of possible linkage that may deserve further investigation.

Alcoholism↗
PubMed1999

Improving the power for disease locus detection in affected-sib-pair studies by using two-locus analysis and multiple regression methods.

In this paper we present a summary of an analysis of the simulated data (Problem 2) for GAW11. We used sib-pair and affected-sib-pair (ASP) methods to evaluate linkage to the mild form of disease at markers across the genome, in data sets of realistic moderate size (containing between 100 and 300 families selected from the simulated replicates). The true 'answers' were known in advance. Although in most cases we were successful in detecting linkage to disease in the correct regions, it was often difficult to distinguish these results from false positives elsewhere in the genome. We used two-locus methods to see whether the significance was improved by simultaneously modeling linkage to two disease loci, and found a modest increase in significance using two-locus methods in several cases.

Genetic Linkage↗
PubMed1999

Evidence of a major gene effect for angiotensinogen among Nigerians.

To dissect the genetic pathway of hypertension, we measured angiotensinogen in 685 members of 186 families recruited from a rural community in southwest Nigeria. Commingling and segregation analyses were carried out. A mixture of two and/or three distributions fits the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provides the best fit to the data and about 13% of the variance was due to the recessive gene segregation.

Adolescent↗
PubMed1999

A test of transmission/disequilibrium for quantitative traits in pedigree data, by multiple regression.

The transmission/disequilibrium (TD) test (TDT), proposed, by Spielman et al., for binary traits is a powerful method for detection of linkage between a marker locus and a disease locus, in the presence of allelic association. As a test for linkage disequilibrium, the TDT makes the assumption that any allelic association present is due to linkage. Allison proposed a series of TD-type tests for quantitative traits and calculated their power, assuming that the marker locus is the disease locus. All these tests assume that the observations are independent, and therefore they are applicable, as a test for linkage, only for nuclear-family data. In this report, we propose a regression-based TD-type test for linkage between a marker locus and a quantitative trait locus, using information on the parent-to-offspring transmission status of the associated allele at the marker locus. This method does not require independence of observations, thus allowing for analysis of pedigree data as well, and allows adjustment for covariates. We investigate the statistical power and validity of the test by simulating markers at various recombination fractions from the disease locus.

Computer Simulation↗
PubMed1999

Linkage information content of polymorphic genetic markers.

The Polymorphism Information Content (PIC) value is often used to measure the informativeness of a genetic marker for linkage studies. The PIC value was first derived for the case of a rare dominant disease, when one of the parents is affected, and is a function of the particular mode of disease inheritance. We first generalize the definition of the PIC value in such a way that it does not depend on the mode of inheritance of the trait being studied, and then develop a Linkage Information Content (LIC) value to measure the informativeness of a marker about the identity-by-descent sharing status of particular types of pairs of relatives. Knowing the LIC value, it is possible to determine the effective number of fully informative pairs in a study when we have incomplete marker information.

Gene Frequency↗
PubMed1999

The Blau syndrome gene is not a major risk factor for sarcoidosis.

BACKGROUND: A genetic predisposition to sarcoidosis has long been postulated, although no specific susceptibility genes are known. Candidate genes for the two granulomatous inflammatory disorders with clinical similarities to sarcoidosis, Blau syndrome and Crohn's disease, have been localized to a 40 centimorgan region spanning the chromosome 16 centromere. PATIENTS AND METHODS: Using a sample of 35 African-American sibling pairs, who both had clinically confirmed sarcoidosis, we tested for genetic linkage between the 16p12-q21 interval (the likely location of the Blau syndrome gene) and sarcoidosis. RESULTS: We found no evidence for linkage to any of the eight markers we tested in the 16p12-q21 interval. Ninety percent of the 16p12-q21 region had a LOD score < -2 for a dominant gene conferring a relative risk of 3 or greater for sarcoidosis. One hundred percent of the region had a LOD score < -2 for a dominant gene with a relative risk of 3.5 or greater or recessive gene with relative risk of 2.5 or greater. Based on simulation results we could not exclude a dominant gene with relative risk < 5 at the 0.05 significance level, nor a recessive gene with relative risk < 3, over the entire 16p12-q21 interval. CONCLUSIONS: While the clinical similarities between Blau Syndrome and sarcoidosis suggest genetic homogeneity between the disorders, we found no evidence for linkage of sarcoidosis to the Blau syndrome locus. Our exclusion results suggest that the Blau Syndrome gene does not have a major effect on sarcoidosis susceptibility.

Adult↗
PubMed1998

A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

Adult↗
PubMed1998

A multivariate logistic model (MLM) for analyzing binary family data.

We consider modeling the familial correlation between 2 related individuals using a multiple logistic regressive model. It is shown that there is a discrepancy in the marginal probability of the second individual. We investigate the conditions under which this discrepancy can be minimized and show how it can have a direct effect on handling missing values and ascertainment. We derive a functional relationship between the parameters in the model that eliminates this discrepancy, hence solving the problems that can arise in the handling of missing values and ascertainment. Because this methodology fails when there are more than 2 related individuals, we present a new model based on a multivariate logistic distribution. Residual familial correlations can be directly related to the parameters of this model. The likelihood for family data under this model is independent of the order in which the family members enter the calculation. The marginal probabilities can be easily computed.

Data Interpretation, Statistical↗
PubMed1998

Using family history information to distinguish true and false positive model-free linkage results.

Genome scans that test for increased marker identity-by-descent sharing between pairs of affected siblings have become increasingly common. These methods do not specify a priori a genetic model for the disease locus and as such lose the ability to specify the parental source of the disease allele. We propose a method that uses family history information to build a more complete model of disease and marker inheritance, while still avoiding specification of the parameters of the disease model of inheritance. One important use for such a model is to test whether a positive linkage result obtained during the course of a genome scan is a true or false positive result. The key to the new test statistics is the interaction between gender-specific marker identity-by-descent sharing and gender-specific family history of disease. The method is useful when the disease locus of interest has a dominant mode of inheritance and a sufficient number of parents are genotyped at the marker locus. If these conditions are met, the proposed tests have good power to differentiate between true and false positive linkage results.

Genetic Diseases, Inborn↗
PubMed1998

Analysis of Swedish male breast cancer family data: a simple way to incorporate a common sibling effect.

Based on a population-based cohort study, Olsson et al. [1993] found significant evidence for elevated incidence of breast and ovarian cancers among female first-degree relatives of men with breast cancer. Using an extension of logistic regressive models we investigate whether, after allowing for multifactorial familial correlations, single locus segregation could be the cause of the elevated incidence in these families. The logit for a given sib in the class D logistic regressive model depends on the order in which affected sibs occur in a sibship. That makes the model less appropriate for the situation where a polygenic component or a common sibling environment may be present, as well as being computationally cumbersome. In this paper, we propose to use the proportion of siblings in a sibship who are affected to quantify a sibling correlation. That not only relaxes the interchangeability problem but also makes the model computationally efficient. We then use this modified class D logistic regressive model for our segregation analysis. Using the proportion of siblings in a sibship who are affected as a covariate resulted in a significantly higher likelihoods in all the models we investigated. We found evidence for a dominant Mendelian gene leading to early age of onset of breast and/or ovarian cancer. This could either be a germline mutation of BRCA2 or a mutation in a gene different from BRCA2.

Adult↗
PubMed1998

Linkage and association.

Methods of both linkage analysis and association analysis may be model-based or model-free. The former are useful for initial exploratory analysis, the latter for more detailed multivariate genometric analysis. Linkage leads to an association, but that association may be solely intrafamilial. Allelic association may be due to pleiotropy, linkage disequilibrium, meiotic drive, selection, or population stratification. Using non-transmitted parental alleles as controls for alleles transmitted to cases, in conjunction with a McNemar-type test, does not detect association in the absence of linkage. Model-based analyses should use models that approximate the complexity of the disease being studied in order to be both robust and powerful.

Case-Control Studies↗
PubMed1998

Restrictions on components of variance for epistatic models.

If a disease is caused by several loci, then the additive variance at each locus may represent only small portions of the total genetic variance, while epistatic variance components may explain a significant amount of the total genetic variance. In this paper we first give simple general formulations to derive all the components of total genetic variance in a random sample for any multilocus model. We then derive these components for a series of fifteen models that have been proposed as being the two-allele two-locus models most likely for disease. We discuss the restrictions and limitations on the penetrance and the gene frequencies, implied by the disease prevalence, for each model. We investigate the relative magnitudes of the components of variance for the various models and show that in six of the models one or other of the epistatic variance components can be larger than each of the other components. It is suggested that investigations be undertaken to develop appropriate sampling and analytical techniques to detect these variance components by linkage analysis.

Epistasis, Genetic↗
PubMed1998

Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis.

OBJECTIVE: In the white population, an association between oculo(dermal) melanocytosis (ODM) and uveal melanoma is well recognized. However, the lifetime prevalence of uveal melanoma in the ODM population is not known. This study was designed to determine the lifetime prevalence of uveal melanoma among patients with ocular melanocytosis. DESIGN: Fifty-six white patients manifesting ODM with uveal melanoma formed the basis of the study. MAIN OUTCOME MEASURES: Published prevalence rates of ODM and uveal melanoma were used for calculations using Bayes' theorem. RESULTS: The lifetime prevalence of uveal melanoma in white patients with ODM is estimated to be 2.6 x 10(-3). The median age at diagnosis of uveal melanoma in the ODM population was similar to a randomly selected population (60.5 years and 62.5 years, respectively). In the vast majority of patients (90%) with ODM-associated uveal melanoma, the uveal melanoma was diagnosed between the ages of 31 years and 80 years. CONCLUSIONS: One of about 400 patients with ODM followed for life is estimated to develop uveal melanoma. Excessive melanocytes in the uveal tract in ODM may provide the biologic basis for susceptibility to the development of uveal melanoma. Patients with ODM should be monitored ophthalmoscopically, especially during the susceptible period, for the development of uveal melanoma. The authors suggest that a national registry of ODM patients be created and prospective data collected to better assess the risk of developing uveal melanoma.

Adolescent↗
PubMed1998

Multiple phenotype modeling in gene-mapping studies of quantitative traits: power advantages.

Genomewide searches for loci influencing complex human traits and diseases such as diabetes, hypertension, and obesity are often plagued by low power and interpretive difficulties. Attempts to remedy these difficulties have typically relied on, and have promoted the use of, novel subject-ascertainment schemes, larger sample sizes, a greater density of DNA markers, and more-sophisticated statistical modeling and analysis strategies. Many of these remedies can be costly to implement. We investigate the utility of a simple statistical model for the mapping of quantitative-trait loci that incorporates multiple phenotypic or diagnostic endpoints into a gene-mapping analysis. The approach considers finding a linear combination of multiple phenotypic values that maximizes the evidence for linkage to a locus. Our results suggest that substantial increases in the power to map loci can be obtained with the proposed technique, although the increase in power obtained is a function of the size and direction of the residual correlation among the phenotypes used in the analysis. Extensive simulation studies are described that justify these claims, for cases in which two phenotypic measures are analyzed. This approach can be easily extended to cover more-complex situations and may provide a basis for more insightful genetic-analysis paradigms.

Chromosome Mapping↗