bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linkage analysis and genetic models for IDDM
Authors: Easton D. F. 
Published: June 2005

AbstractThe multiplex insulin‐dependent diabetes mellitus (IDDM) families have been examined for linkage with the human leukocyte antigen (HLA), Gm, Km, and insulin loci. For the last three, no evidence of linkage (as measured by haplotype sharing in affected siblings) was found. For HLA, strong evidence of linkage was demonstrated, as expected from previous studies of both haplotype sharing and HLA association. The haplotype sharing in affected siblings from this and previous studies would explain a relative risk of about 3.7 in the sibling of an affected individual (95% confidence limits 2.8 to 5.4), considerably less than the values of 10–15 given by epidemiological studies. This discrepancy may be explained by other predisposing genes unlinked to HLA, or be due to common environmental factors. Analysis conditional on the affection status of all individuals, and on the parental HLA haplotypes clearly rejects both a dominant and recessive mode of inheritance in favor of a two‐allele model with a reduced risk for heterozygotes, and provides some support for a three‐allele model.Some evidence of age effects was found; in particular there was some suggestion of greater haplotype sharing in siblings both affected at a young age, and there was some suggestion that individuals with the predisposing HLA‐DR3/DR4, DR3/DRx, and DR4/DRx genotypes were affected at a younger age. These results may be diagnostic artifacts, however, and need investigation in future studies.
Remarks on ascertainment
Authors: Ewens W. J. , Shute Nereda C. E. 
Published: June 2005

AbstractGenetic Analysis Workshop data come from various sources, with possibly different ascertainment procedures in each. It is plausible that classical ascertainment models do not accurately describe the ascertainment process in each data source. For this reason, we review the biases which can arise from an incorrect specification on the ascertainment process and discuss their relevance for the GAW5 data analysis.
HLA DR4‐DQw3.1 and 3.2 haplotypes among insulin‐dependent diabetics and their unaffected sibs in the GAW5 data
Authors: Gogolin Kathryn J. , Spielman Richard S. 
Published: June 2005

AbstractAlmost all human leukocyte antigen (HLA) haplotypes positive for HLA‐DR4 also carry the DQw3 specificity, which appears in one of two allelic forms, DQw3.1 or DQw3.2. Previous studies have shown that the frequency of the HLA DR4‐DQw3.2 allele is approximately 95% among DR4‐positvie haplotypes of insulin‐dependent diabetics (IDDM), but only 70% in DR4‐positive haplotypes of unaffected individuals. Because this difference could be due to ethnic heterogeneity, it is important to establish whether the frequency of the DQw3.2 allele is also increased when haplotypes of diabetics are compared to those of “matched” unaffected individuals, as can be done within families. We have used the Genetic Analysis Workshop 5 (GAW5) data for this purpose. In every family, each parental DR4‐bearing haplotype was categorized as “IDDM” if it appeared in any affected parent or offspring, or as “control” if not. When this was done, the frequencies of the DQw3.2 and 3.1 allele in 80 IDDM haplotypes were 94% and 6% respectively but 67% and 33% in 15 control haplotypes. This difference between the two kinds of haplotypes is highly significant (P < 0.005).
Clues to IDDM pathogenesis from genetic and serological traits in multiply affected families
Authors: Klitz William , Kuhner Mary K. , Robinson Wendy , Esposito Michael , Thomson Glenys 
Published: June 2005

AbstractA scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5′ insulin locus (INS) in insulin‐dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.
Combined segregation and linkage analysis for IDDM and HLA‐DR under several ascertainment assumptions
Authors: Pascoe Leigh , Sherman Stephanie , Wu Danny , Becker Murray , Falk Catherine 
Published: June 2005

AbstractCombined segregation and linkage analysis of the Genetic Analysis Workshop 5 (GAW5) data suggests a complex basis for susceptibility to insulin‐dependent diabetes mellitus (IDDM). One susceptibility gene, linked to the HLA‐DR region, is additive on the liability scale (d = .49 ± .15,t = 2.9 ± .6) with a gene frequency q = .30 ± .03. A second locus, with a gene frequency of q = .07 ± .02, which is recessive and unlinked to HLA, is also suggested by the analysis. The ascertainment correction used has little effect on the results, presumably because most of the information comes from the cosegregation of HLA alleles and disease status. The results are consistent with a direct involvement of the HLA‐DR region in susceptibility, but are not a proof of it.
Autoimmune thyroid disease in type I diabetic families
Authors: Payami H. , Joe S. , Thomson G. 
Published: June 2005

AbstractThe prevalence rate for autoimmune thyroid disease (ATD) is about 30 times higher in the type I diabetic (IDDM) families that were ascertained for Genetic Analysis Workshop 5 (GAW5) than in the general population. Two approaches were used to study the clustering of ATD and IDDM in these families: (1) HLA haplotype sharing in sib pairs in which one has IDDM and other has ATD was analyzed with the genetic interrelationship method. The hypotheses of different alleles (at the same locus or at different loci) were rejected. Thus there must exist at least one common allele that predisposes to both IDDM and ATD. (2) The DR genotype frequencies suggest that in the GAW5 families two alleles may be predisposing to ATD; a recessive DR3‐associated allele and a dominant DR4‐associated allele.
Description of the National Institute of Mental Health family study of affective disorders
Authors: Gershon Elliot S. , Goldin Lynn R. , Guroff Juliet J. , Hamovit Joel R. 
Published: June 2005

AbstractThe NIMH family study consisted of 172 probands with affective disorder and 43 normal control probands. Psychiatric disorders were diagnosed in relatives over the age of 18 using Research Diagnostic Criteria based on personal interviews, medical records, and family history information. Some families were also genotyped for red cell, serum, and HLA marker loci. Previous analyses of these data have shown that affective disorders aggregate in families. Segregation analyses have not been able to define the mode of inheritance.
Toronto‐Rochester depression study of 116 HLA‐typed kindreds
Authors: Stancer H. C. , Weitkamp L. R. , Persad E. , Flood C. , Jorna T. , Guttormsen S. A. , Yagnow R. L. 
Published: June 2005

AbstractThe Toronto‐Rochester Depression study consisted of 116 pedigrees ascertained for multiple cases of major affective disorders. Among the 857 psychiatrically evaluated family members, of whom more than 85% were given a structured interview, 363 had major affective disorder by Research Diagnostic Criteria and 385 had no history of psychological aberration. HLA region genes were typed in 804 of these persons.
Robustness of the unified model to shared environmental effects in the analysis of dichotomous traits
Authors: Demenais Florence , Abel Laurent 
Published: June 2005

AbstractSimulation studies were conducted to assess to what extent the conclusions of segregation analysis, performed under the unified model, can be affected by the presence of unmeasured environmental factors shared by family members. Dichotomous data were generated on six‐member nuclear families under two variants of the mixed model, incorporating environmental effects shared by all family members. When the generating model includes a polygenic component and a shared environmental effect, there is false detection of a major gene, especially when the joint likelihood of parents' and offspring's phenotypes is computed. The proportion of false conclusions increases as the shared environmental effect increases. On the other hand, the presence of a shared environmental effect in addition to a major gene component does not alter the detection of the major gene nor the transmission probability estimates, which are close to the expected Mendelian values. The rejection of the Mendelian transmission hypothesis, as observed in familial analyses of affected disorders, might be the result of mechanisms other than those considered here, such as more complex sources of environmental resemblance or a possible genetic heterogeneity.
Performance of linkage analysis under misclassification error when the genetic model is unknown
Authors: Martinez Maria , Khlat Myriam , Leboyer Marion , Clerget‐Darpoux Françoise 
Published: June 2005

AbstractLinkage analysis of complex diseases raises a number of important methodological problems. One of them concerns the clinical classification of disease phenotypes. In this study, we investigate the effects of false positive misclassification on the estimation of the recombination fraction and on the power and the robustness of tests for linkage. These effects are investigated 1) when the genetic model of the trait locus is known; and 2) when it is unknown, by maximizing the likelihood of the marker configuration given the disease status in the family. Results show that linkage analysis of misclassified data leads to an overestimation of the recombination fraction and a loss of power of the linkage test. The results are quite similar in both situations. However, the linkage test itself is robust to this kind of misclassification error.
HLA may be involved in resistance and susceptibility to affective disorders
Authors: Payami H. , Dubay C. , Valenzuela R. Carrero 
Published: June 2005

AbstractThe role of HLA in susceptibility to affective disorders was assessed by sib pair linkage analysis and by association studies. Unipolar Disorder (UD) and Bipolar Disorder (BD) were studied separately. Both the sib pair data and the antigen frequency distribution suggested an HLA‐linked susceptibility to UD. For BD however, the HLA haplotype sharing distribution in sib pairs was random, but the antigen frequencies suggested at least one positive association and one negative association with HLA. The lack of evidence for linkage to HLA from sib pairs may have been due to the genetic heterogeneity of BD.
Genetic epidemiology of bilateral breast cancer: A linkage analysis using the affected‐pedigree‐member method
Authors: Haile Robert W. , Goldstein Alisa M. , Weeks Daniel E. , Sparkes Robert S. , Paganini‐Hill Annlia , Rao D. C. , Vogler G. P. 
Published: June 2005

AbstractWe used the affected‐pedigree‐member (APM) method to conduct linkage analyses on 19 pedigrees in which the probands had premenopausal bilateral breast cancer. This method analyzes all affected pairs of relatives, as opposed to siblings only, and incorporates into the analyses information on the frequency of marker alleles. Fourteen codominant marker systems were evaluated in two separate analyses. In the first, only premenopausal cases of breast cancer were coded as affected because we assumed that postmenopausal cases were due to a different etiology. In the second analysis, all cases of breast cancer were coded as affected, irrespective of menopausal status. In the premenopausal‐cases‐only analysis, we observed evidence suggestive of nonindependent segregation for C3 and ESD. In the all‐cases analysis, we observed much weaker evidence for C3 and ESD and noted a suggestion of nonindependent segregation for AMY2 and PGM1.
Estimation of individual genetic and environmental factor scores
Authors: Boomsma D. I. , Molenaar P. C. M. , Orlebeke J. F. , Rao D. C. , Vogler G. P. 
Published: June 2005

AbstractImplicit in the application of the common‐factor model as a method for decomposing trait covariance into a genetic and environmental part is the use of factor scores. In multivariate analyses, it is possible to estimate these factor scores for the communal part of the model. Estimation of scores on latent factors in terms of individual observations within the context of a twin/family study amounts to estimation of individual genetic and environmental scores. Such estimates may be of both theoretical and practical interest and may be provided with confidence intervals around the individual estimates. The method is first illustrated with simulated twin data and next is applied to blood pressure data obtained in a Dutch sample of 59 male adolescent twin pairs. Subjects with high blood pressure can be distinguished into groups with high genetic or high environmental scores.
Evolution of the Pittsburgh studies of the epidemiology of insulin‐dependent diabetes mellitus
Authors: Kuller Lewis H. , Becker Dorothy J. , Cruickshanks Karen J. , Dorman Janice S. , Eberhardt Mark S. , Drash Allan L. , LaPorte Ronald E. , Lipton Rebecca , Moy Claudia , O'Leary Leslie A. , Orchard Trevor J. , Rewers Marian , Songer Thomas , Tajima Naoko , Trucco Massimo , Wagener Diane , Spielman R. S. 
Published: June 2005

AbstractThe Pittsburgh project evaluating the epidemiology and etiology of insulin‐dependent diabetes mellitus (IDDM) is currently one of the large ongoing studies of childhood diabetes. This paper traces the evolution of the project, from the initial basic epidemiologic approach in the early 1980s, to the current thrust where complex molecular genetic approaches are being incorporated into population‐based research. The epidemiology models employed in the Pittsburgh project are similar to those that could be used in many areas of chronic disease research. The integration of immunogenetics into epidemiology produces a powerful approach for understanding the complex interaction of host susceptibility and environmental agents that contribute to the development of IDDM.
An epidemiologic approach to gene‐environment interaction
Authors: Ottman Ruth , Rao D. C. 
Published: June 2005

AbstractThis paper illustrates how epidemiologic principles can be used to investigate relationships between genetic susceptibility and other risk factors for disease. Five plausible models are described for relationships between genetic and environmental effects, and an example of a simple mendelian disorder that fits each model is given. Each model leads to a different set of predictions about disease risk in individuals with the genetic susceptibility alone, the risk factor alone, both, or neither. The risk predictions for the different models are described, and research designs for testing them are discussed.
Note on linkage analysis when the mode of transmission is unknown
Authors: Neuman Rosalind J. , Rice John P. , Rao D. C. 
Published: June 2005

AbstractA major difficulty in a linkage analysis arises from the necessity of specifying the mode of inheritance prior to analysis. For a complex disease, such as those encountered in psychiatric illnesses, the mode of inheritance is generally not known in advance. Consequently, some estimation procedure is often combined with linkage analysis to circumvent this. We discuss several precautions that should be taken when using traditional statistical testing methods: correction of the likelihood for the method of sampling families and the computation of the lod score. We analyze simulated data with pedigrees selected under a sampling scheme approximating single ascertainment. In this situation, the severity of the above problems is attenuated.
Extensions to sib‐pair linkage tests applicable to disorders characterized by delayed onset
Authors: Dawson Deborah V. , Kaplan Ellen B. , Elston Robert C. , Rao D. C. 
Published: June 2005

AbstractExtensions of the approach to sib‐pair linkage tests developed by Haseman and Elston [Behav Genet 2:3–19, 1972] are proposed which incorporate information on age of onset and age at examination. Alternate sources for the age of onset corrections are described, including models for the estimation of parameters associated with the age of onset distribution. Simulation is used to examine the performance of the approach when applied to a dominant disorder of late onset for a range of recombination fractions ranging from very tight linkage to free recombination. For each set of genetic parameters, 2,000 samples of 50 four‐member sibships were generated under a complete ascertainment model to investigate power and Type I error, and to compare variants of the proposed technique. Results with and without age‐of‐onset correction are compared to each other and to those obtainable if penetrance were complete, i.e., if there were no intervening age‐of‐onset phenomenon.Results from simulation studies show that significance probabilities are enhanced in the presence of linkage when age‐of‐onset extensions are used. The proposed methods are associated with acceptable levels of Type I error, and substantive gains in power are obtained when data related to age of onset and age at examination are incorporated into the analysis.
Genetics of subdivided populations and its relationships with certain measures of association
Authors: Li C. C. , Vogler G. P. 
Published: June 2005

AbstractUnlike inbreeding, population subdivision affects different genotypes differently for multiple alleles, so that the simple relationship between inbreeding and subdivision for two alleles no longer holds for all genotypes. In this communication, the detailed effects of subdivision have been studied for three alleles with results easily generalized to any number of alleles. Then an average effect of subdivision is proposed. This average effect of subdivision is found to play the same role as the inbreeding coefficient for multiple alleles, so that the overall relationship between inbreeding and subdivision may be reestablished again. In the final section, we discuss the relationship of the genetic result with measures of association of square contingency tables arising from epidemiological, social studies, educational and psychological studies.
Investigating genomic imprinting and susceptibility to insulin‐dependent diabetes mellitus: An epidemiologic approach
Authors: McCarthy Bridget J. , Dorman Janice S. , Aston Christopher E. , Vogler G. P. 
Published: June 2005

AbstractChildren of fathers with insulin‐dependent diabetes mellitus (IDDM) are at greater risk of developing the disease than are children of IDDM mothers, reasons for which are currently unknown. To explore the possibility that genomic imprinting contributes to this phenomenon, 1,774 families with at least one IDDM child diagnosed before the age of 17 years and between 1950 and 1981 from the Children's Hospital at Pittsburgh IDDM Registry were evaluated. Approximately 1% of the mothers and 2.9% of the fathers were reported to have IDDM diagnosed before the age of 36 years (P < 0.001). Excluding IDDM probands, the IDDM recurrence risk to siblings in families with an IDDM father was greater than that in families with an IDDM mother or in those with neither parent affected. Lifetable analyses revealed that among all children of diabetic fathers (probands included), there was a greater prevalence of IDDM, through age 30 years, for sons compared to daughters (59.5% vs. 34.1%, P = 0.02). However, there was no significant sex difference in the prevalence of IDDM among children of affected mothers (41.1% vs. 45.5%, P >0.05). These data are not consistent with the genomic imprinting hypothesis and suggest that other genetic and/or environmental factors contribute to the increased risk for children of IDDM fathers.
Commentary: The affected sib‐pair method in the context of an epidemiologic study design
Authors: Khoury Muin J. , Flanders W. Dana , Lipton Rebecca B. , Dorman Janice S. , Vogler G. P. 
Published: June 2005

AbstractThe purpose of this commentary is to provide a framework for using the well‐known sib‐pair methodology in the context of epidemiologic study designs. Using examples from the Pittsburgh family studies of insulin‐dependent diabetes mellitus, we illustrate that the sib‐pair method can be used in family‐based epidemiologic studies. In a cohort study, unaffected relatives of probands ascertained from well‐defined populations are followed for disease development. Disease risks are indentical by descent (ibd) then stratified according to the number of alleles at one or more loci (0, 1, 2) that are identical by descent (ibd) with the proband. In the absence of linkage between the marker locus and the disease locus, disease risks are expected to be identical in the three groups. Measures of relative risk can be computed (with share‐0 as baseline group). In a case‐control study, relatives of probands that become affected (cases) are compared to a sample of relatives of probands that stay unaffected (controls) with respect to the number of alleles ibd with the proband. Measures of odds ratio can be computed (with share‐0 as baseline group). In both cohort and case‐control approaches, covariates including other genetic markers and environmental exposures can be evaluated in relation to disease risk and also for evidence of interaction with the specific marker of interest using stratified and multivariate analyses. Family‐based epidemiologic studies allow investigators to study, in a single design, the role of environmental factors and specific gene loci in the etiology of diseases.
Detection of linkage under heterogeneity: Comparison of the two‐locus vs. admixture models
Authors: Goldin Lynn R. , Vogler G. P. 
Published: June 2005

AbstractLinkage analysis under the two‐locus model and the admixture model was compared on pedigree data for a common disease simulated under a model of genetic heterogeneity. The ascertainment of families was designed so that the samples had a large proportion of families segregating for both disease loci. The two‐locus linkage analysis model did not demonstrate increased power of detecting linkage or more accurate estimates of the recombination fraction, θ than did the admixture model linkage analysis. When a sample was purposely chosen so that all of the families were segregating for both loci, then the two‐locus lod score analysis was better. However, the increased power depended on assuming the correct gene frequency for the linked locus. It can be concluded that under the conditions of genetic heterogeneity examined here, testing for linkage under the admixture model is the preferred method of analysis. However, this is not a general conclusion that can apply to all two‐locus disease models. Published 1992 by Wiley‐Liss, Inc.