bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic epidemiology of Menkes disease
Authors: Horn Nina , Morton Newton E. , Rao D. C.
Published: June 2005

Copper incorporation studies were performed on individuals from 58 pedigrees, comprising 140 sibships. As previously reported, there is considerable overlap between heterozygotes and normal homozygotes. Segregation analysis supports recessive inheritance of disease, with residual heritability for 64Cu uptake in cultured cells. The population frequency of sporadic cases is compatible with the 1/3 expected for an X‐linked lethal with equal mutation rates in egg and sperm, which implies a mutation rate of 6.7 × 10−6/gamete/generation. The parameters estimated here are likely to provide the best basis for genetic counseling until more reliable carrier tests are performed on a systematic sample from a large, defined population.
Description of a large pedigree with an adverse lipoprotein cholesterol phenotype: The Bogalusa Heart Study
Authors: Rosenbaum Peter A. , Amos Christopher I. , Shear Charles L. , Elston Robert C. , Sellers Thomas A. , Srinivasan Sathanur R. , Berenson Gerald S. , Rao D. C.
Published: June 2005

A large pedigree (N = 356) with a high prevalence of heart disease and associated adverse lipoprotein phenotype was studied. The adverse lipoprotein phenotype is characterized by both low levels of high‐density‐lipoprotein cholesterol (HDL‐C) alone (16.3%) and in combination with other adverse lipoprotein levels (12.8%). In all, 44.2% of all pedigree members had at least one adverse lipoprotein level. Analysis of mating types showed that all lipids and lipoproteins possess familial clustering with 25–36% of offspring above median levels when both parents had levels below the median, while 67–83% had levels above the median when both parents had levels above the median. Using adjusted lipid and lipoprotein levels, a statistically significant linear trend was found between the degree of relationship to pedigree members with heart disease, and both the low‐density‐lipoprotein cholesterol/high‐density‐lipoprotein cholesterol (LDL‐C/HDL‐C) ratio (P < .05), and the very‐low‐density‐lipoprotein cholesterol (VLDL‐C; P < .01) level. A similar analysis using the prevalence of adverse lipoprotein levels as the dependent variable and degree of relationship to heart diseased pedigree numbers as the independent variable showed significant (P < .05) relationships with VLDL‐C and the LDL‐C/HDL‐C ratio. Further genetic analyses of this pedigree may reveal genetic mechanisms responsible for the familiality of lipoprotein levels in this pedigree.
Linkage analysis of Von Recklinghausen neurofibromatosis: Chromosomes 4 and 19
Authors: Dietz Jeanne N. , Robbins Tim , Cannon Lisa A. , Schwartz Charles E. , Carey John C. , Johnson John P. , Kivlin Jane , Skolnick Mark H. , Rao D. C.
Published: June 2005

This report describes a study that examines the hypotheses of genetic linkage between the autosomal dominant disorder neurofibromatosis (NF) and loci on human chromosomes 4 and 19. Twelve Utah families were evaluated for evidence of possible linkage of NF to six known markers on chromosome 4 and five markers on chromosome 19. Due to previous reports suggesting tight linkage of NF to the GC locus on chromosome 4 and the C3 (linked to myotonic dystrophy) locus on chromosome 19, these two markers were of particular interest. For the Utah families the cumulative LOD score for GC was −4.81 (r̂ = 0.05). Cumulative LOD scores were −0.90 (r̂ = 0.05) and −1.01 (r̂ = 0.05) for C3 serum determinations and a C3 DNA polymorphism respectively. Linkage data is also included on all individual informative families for the GC and C3 loci to specifically address the question of heterogeneity. Linkage data is consistent with, but does not strongly support, the existence of heterogeneity implicating both the GC locus on chromosome 4 and the C3 locus on chromosome 19. A compilation of cumulative LOD scores from this and other current linkage studies produces values that in the absence of heterogeneity refute previous reports for tight linkage of NF to GC and to C3.
Estimation of linkage disequilibrium from conditional haplotype data: Application to β‐globin gene cluster in American blacks
Authors: Chakraborty Ranajit , Rao D. C.
Published: June 2005

Simple estimators of gene frequencies and linkage disequilibria are proposed when haplotype data are available from four parental chromosomes of a child (or fetus) for whom genetic counseling is sought for a disease condition. The method is illustrated with restriction site polymorphisms associated with sickle‐cell anemia (Hb‐βS) gene as surveyed in genetic counseling data from American blacks. The method suggested here is shown to be useful in testing for the significance of interactions of site‐specific variations of any order in the chromosomal region assayed.
Multiple regression analysis of twin data obtained from selected samples
Authors: LaBuda Michele C. , Defries J. C. , Fulker D. W. , Rao D. C.
Published: June 2005

The multiple regression analysis of twin data in which a cotwin's score is predicted from that of a proband (the member of a twin pair selected because of a deviant score) and the coefficient of relationship provides a powerful test of genetic etiology (DeFries and Fulker: Behav Genet 15:467–473, 1985). Moreover, when an augmented model containing an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance owing to shared environmental influences (c2) are also obtained. In the present paper, the expected partial regression coefficients estimated from these models are derived, and the flexibility of the general approach is illustrated. An extended model is formulated for the analysis of data from combined samples of affected and control twin pairs that yields tests for differential h2 and c2 in the two groups as well as pooled estimates of these parameters. The application of these models is illustrated by an analysis of data from reading‐disabled and control twin pairs. Because of the ease, flexibility, and utility of the multiple regression analysis of twin data, it is an appealing alternative to more traditional model‐fitting approaches.
Goodness‐of‐fit tests for locus order in three‐point mapping
Authors: Ott Jurg , Lathrop G. Mark , Rao D. C.
Published: June 2005

For the case of three‐point linkage analysis, a simple goodness‐of‐fit test is proposed to test the order of gene loci. To use it for testing one locus order against another, one may apply the principle that evidence for one order comes from lack of fit of the observations to the other order. With n = 30 offspring from a phase known triple backcross mating, at a recombination fraction of 20% between adjacent loci, the test achieves a power of 80% (5% significance level). Interference (real interference as well as interference assumed in the analysis) increases power.
Apolipoprotein genetic variation in the assessment of atherosclerosis susceptibility
Authors: Hegele Robert A. , Breslow Jan L. , Cloninger C. Robert
Published: June 2005

Apolipoproteins are the protein constituents of lipoproteins, the particles that transport cholesterol and triglycerides in the plasma. Numerous epidemiologic studies have associated variations in plasma levels of lipoproteins and apolipoproteins with the development of atherosclerosis. Furthermore, genetic variations in lipoproteins and apolipoproteins have been associated with disorders of lipid metabolism. Recent advances in biochemical and molecular genetic methods have resulted in an increased understanding of interindividual variations in lipoprotein metabolism and of their relationship to atherosclerosis and the dyslipoproteinemias. In particular, certain DNA restriction fragment length polymorphisms of the apolipoprotein genes have, in the last few years, been associated with atherosclerotic diseases and dyslipoproteinemias. We believe that genetic markers, when used in conjunction with traditional clinical and biochemical determinations, may one day be useful in predicting atherosclerosis susceptibility in the general population.
Endogenous sex hormone levels and breast cancer risk
Authors: Begg Lisa , Kuller Lewis H. , Gutai James P. , Caggiula Arlene G. , Wolmark Norman , Watson Charles G. , Rao D. C.
Published: June 2005

Sex‐steroid hormones are a major determinant of the risk of breast cancer. We evaluated the relationship between obesity and endogenous estrogen levels in 79 healthy, postmenopausal women. Thirty‐nine of the women were siblings of patients with postmenopausal‐onset breast cancer; the remaining women were age matched (± 10 yr) controls. Our hypothesis was that the siblings of the breast cancer patients would weigh more and that this excess weight would lead to higher serum estrone levels. The choice of unaffected family members of breast cancer patients reduces the concern that results may have been influenced by the cancer rather than antecedent to its development. Our findings demonstrated a statistically significant excess estrone level in the siblings compared to the controls (58.9 vs 47.8 pg/ml, P=0.005). The siblings weighed 4.3 kg more than the controls. Matched pairs analysis (sibling—control), adjusting for weight, also showed significant differences in serum estrone levels. These differences were observed despite comparability in dietary intake, medication use, and personal medical history. These findings represent the first time that higher estrogen levels have been measured in siblings of postmenopausal breast cancer patients. This observation may represent an important link in our understanding of the relationship between genetic and environmental risk factors of breast cancer. One approach to subsequent genetic studies of breast cancer may be to focus on the possible biological determinants such as sex‐steroid hormone level receptors, oncogenes, and gene products and not on the “familial aggregation” of breast cancer.
Classification of rheumatoid arthritis: The importance of including data from the siblings
Authors: Walker D. J. , Stephenson A. M. , Griffiths I. D. , Roberts D. F. , Rao D. C.
Published: June 2005

A discriminant analysis has been applied to physical and laboratory data on a series of 37 patients with rheumatoid arthritis (RA). Good discrimination was found between RA when it was associated with organ‐specific autoimmune phenomena and when it was not. When data from other members of the families was included there was consistently better discrimination than when using data from the patients alone. The results suggest that future studies of classification of variable diseases should include study of relatives.
Tests of linkage and heterogeneity in Mendelian diseases using identity by descent scores
Authors: Chakravarti Aravinda , Badner Judith A. , Li Ching Chun , Rao D. C.
Published: June 2005

When linkage between a recessive Mendelian disease and specific candidate genes is investigated, identity by descent scores in affected sib pairs may be used for tests of linkage and heterogeneity. Statistical tests for performing this analysis are presented. The efficiency and statistical power of the method are also investigated using computer simulations.
Sporadic vs familial classification given etiologic heterogeneity: I. Sensitivity, specificity, and positive and negative predictive value
Authors: Kendler Kenneth S. , Cloninger C. R.
Published: June 2005

Environmental factors are etiologically important in many non‐Mendelian familial disorders in man. Because such disorders often occur as “sporadic” cases, (ie, an affected individual with no affected relatives), it is tempting to assume that such cases represent an “environmental” form of the disorder. This paper presents an evaluation of the sensitivity, specificity, and positive and negative predictive power (PPV and NPV) of this “sporadic vs familial classification.” The model assumes etiologic heterogeneity with a subpopulation of cases due to a “major” environmental event acting independent of genotype and the remaining cases resulting from a generalized single major locus (SML). Sibship size is modeled by a truncated negative binomial distribution. For rare disorders, this classification has high sensitivity and NPV but low specificity and PPV. As the disorder becomes more common, sensitivity and NPV fall while specificity and PPV rise. The power of the method increases substantially with increasing sibship size up to four or five, but further increases in power are minimal. MZ twins add considerable power to the method but aunts and uncles add little if anything. Both a correlational (phi) and an agreement‐based (kappa) statistic indicate that, under most realistic circumstances, the relationship between etiology and family history is modest.
Nonrandom sampling in genetic epidemiology: Maximum likelihood methods for multifactorial analysis of quantitative data ascertained through truncation
Authors: Rao D. C. , Wette R. , Eaves Lindon J.
Published: June 2005

Three types of nonrandom sampling of family data are described, and appropriate maximum likelihood methods are proposed for each. The three types arise depending on whether the selection of probands, based on truncation, is applied directly to the phenotypic distribution, to the distribution of a correlated trait, or to the liability distribution of an associated disease. Family data ascertained through random and nonrandom sampling can be analyzed together in a unified approach. Results of a Monte Carlo study are presented that demonstrate the utility of the proposed methods. In particular, likelihood ratio tests of null hypotheses are shown to be distributed as chi‐square, even in samples as small as 50 families (with variable sibship size).
Exclusion of autosomal dominant dystonia gene from large regions of chromosomes 11p, 13q, and 21q by multi‐point linkage analysis
Authors: Kramer P. L. , Ozelius L. , Gusella J. F. , Fahn S. , Kidd K. K. , Breakefield X. O. , Boerecki I. B.
Published: June 2005

Multi‐point linkage analyses of autosomal dominant form of torsion dystonia with linkage groups on chromosomes 11p, 13q, 21q are reported. Analyses are based on family data from a single, large, non‐Jewish pedigree. Large portions of chromosomes 11p and 13q, and virtually the entire long arm of chromosome 21 are excluded from linkage with dystonia. Practical aspects of designing multipoint analyses are discussed.
Power of the affected‐sib‐pair method for heterogeneous disorders
Authors: Goldin Lynn R. , Gershon Elliot S. , Borecki I. B.
Published: June 2005

We have examined the sample sizes required to detect linkage using the affected‐sib‐pair (ASP) method for major psychiatric disorders that are characterized by population prevalences of 1–7%, decreased penetrance, phenocopies, and heterogeneity. In addition, the nature of these illnesses makes large, multigenerational pedigrees difficult to collect. We calculated the sample sizes needed to have 80% power of finding linkage (with a type I error rate of 5%) under dominant and recessive models with incomplete penetrance and allowing for recombination rates of up to 10% between the disease gene and marker gene. We have assumed that the identical‐by‐descent (IBD) status of ASPs is known exactly. For a disease like schizophrenia (1% population prevalence), if 50% of families are linked to a marker locus at 10% recombination, then 60 and 120 pairs are needed under recessive and dominant inheritance, respectively. For a disorder such as major affective disorder (7% population prevalence), the sample size is similar if the inheritance is recessive, but larger (160 pairs) if the inheritance is dominant. We conclude that this method may be a reasonable alternative for psychiatric disorders, especially to confirm that a linkage found in a specific pedigree or population isolate is also present in the general population.
Segregation analysis of juvenile myoclonic epilepsy
Authors: Greenberg David A. , Delgado‐Escueta Antonio V. , Maldonado Hector M. , Widelitz Heidi , Rao D. C. , Borecki I. B.
Published: June 2005

We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of “epilepsy” and the trait of “epilepsy‐plus‐EEG abnormalities”, since EEG abnormalities are frequently found in the clinically unaffected sibs of JME patients. We tested several modes of inheritance including the fully penetrant recessive and several two‐locus models. We could reject all models tested (fully penetrant single‐locus and two‐locus models) when abnormal EEGs were classified as “unaffected”. We could also reject the fully penetrant single locus models when family members with abnormal EEGs were considered “affected”. We also rejected the two‐locus model where the inheritance at both loci was dominant. The two‐locus model where both loci showed recessive inheritance could not be rejected, nor could the model where one locus was dominant and the other recessive. Our results suggest that the underlying predisposition for JME is genetically determined and is partially reflected in the abnormal EEGs found in clinically unaffected family members.
Linkage information and bias in the presence of interference
Authors: Bishop DT , Thompson EA , Rao D. C.
Published: June 2005

Although interference is an important biological phenomenon, linkage analyses often ignore it for computational efficiency. In this paper we examine the effects of ignoring interference on estimates of recombination fraction, and the power of statistical tests to detect interference. We show that for gametes from phase‐known triple heterozygotes, no bias in the recombination fraction for adjacent loci results from the assumption of lack of interference even if interference is present. However, for samples from pairwise informative samples, there is bias introduced. An analytical form for this bias is obtained.
Some biological and social factors of risk associated with the birth of pre‐term infants
Authors: Livshits G. , Davidi L. , Kobyliansky E. , Levi Y. , Ben‐Amitai D. , Merlob P. , Rao D. C.
Published: June 2005

The main purpose of the present study was to evaluate the effects of factors associated with spontaneous pre‐term births so that the high risk woman could be identified before or at early stages of pregnancy. For this purpose, we have compared the measurements of 21 anthropometric traits and mean fluctuating asymmetry over 8 bilateral anthropometric traits, as well as age, occupation, education, previous obstetric history, complications during pregnancy, medicines received during and after pregnancy and some others in women who delivered babies of short (26–36 wk, n = 113 ind.) and normal gestational age (n = 103). Diseases and mean fluctuating asymmetry of eight morphological traits in the newborn infants themselves were also studied.

Both univariate and multivariate analyses were carried out and these were in agreement, showing a highly significant increase in the morbidity rate (especially of respiratory diseases) among pre‐term infants and in complications during pregnancy in their mothers. Among other variables associated with the current pre‐term birth were previous spontaneous pre‐term births, suggesting their special risk value. The estimate of the sib correlation in gestational age on the liability scale was about 0.63. Spearman and Pearson correlations in gestational age for siblings were 0.34 and 0.31, respectively.
Cell surface markers and cellular immune response associated with rheumatic heart disease: Complex segregation analysis
Authors: Rich SS , Gray ED , Talbot R. , Martin D. , Cairns L. , Zabriskie JB , Braun D. , Regelmann WE , Vogler G. P.
Published: June 2005

A series of functional and cell surface markers associated with a significantly increased risk of rheumatic heart disease were analyzed for the contribution of genetic factors in their presence. Peripheral blood lymphocytes from nine large kindreds from the New Zealand Maori, Polynesian, and Caucasian populations were isolated, purified, and evaluated with lymphocyte surface markers (monoclonals 83S.19.23 and D8103), as well as studied for blastogenic response to a purified group A streptococcal extracellular product, blastogen A. Segregation analysis of blastogenic response and percent of cells positive for these cell surface markers was consistent with genetic control by single major genes; however, the contribution by polygenes varied by marker, indicating heterogeneity of genetic control of identification of cell surface glycoproteins and blastogenic response to streptococcal products.
Genetic analysis of IDDM: Summary of GAW5 IDDM results
Authors: Spielman Richard S. , Baur Max P. , Clerget‐Darpoux Françoise
Published: June 2005

This paper summarizes the analyses by participants in the insulin‐dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5). The data were obtained from 94 families with two or more IDDM sibs. Topics treated in the Workshop analysis included the following: methods for detecting associations and linkage, the contribution by HLA‐linked and ‐unlinked loci to IDDM susceptibility, the role of subtypes of the serologically defined HLA specificities, the implications of associated diseases other than IDDM in the families, the significance of antibodies to Coxsackie viruses, and of autoantibodies to pancreatic islet cells and insulin, and the use of genetic models to analyze the inheritance of IDDM.

There was agreement that an explanation for the data on multiplex IDDM families must include the following features: (1) There is a susceptibility locus (or loci) in the HLA region. (2) The HLA‐linked factor(s) are more complex than a single licus with one disese and one nondisease allele. (3) There is additional familial correlation beyond that explained by HLA‐linked susceptibility, which may be genetic and/or environmental.

With regard to the third feature, IDDM‐GAW5 included data on variation in Gm haplotypes and at the insulin gene, two regions unlinked to HLA. However, there was no direct evidence (i.e., from marker segregation) that the additional factor, if genetic, is linked to either Gm or the insulin gene. Nevertheless, a significant difference was found between “diabetic” and “control” insulin genes with respect to frequency of class 1 alleles for the 5′ flanking polymorphism, strongly suggesting linkage.
Testing genetic models for IDDM by the MASC method
Authors: Clerget‐Darpoux Françoise , Babron Marie‐Claude
Published: June 2005

The MASC method has been applied to the GAW5 data. The method uses the simultaneous information on association and segregation of the HLA marker with the disease and the segregation of the HLA marker in affected families. It also takes into account the differential risk for parents of a patient, as well as the different HLA haplotype sharing, according to the HLA genotype of the patient. The goodness of fit of several genetic models has been tested. The observed data are not compatible with a two‐allele, one‐locus model, but they fit a three‐allele, one‐locus model and a complementation two‐locus model if additional familial correlation is allowed.
Linkage analysis and genetic models for IDDM
Authors: Easton D. F.
Published: June 2005

The 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

Genetic 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

Almost 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

A 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

Combined 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

The 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

The 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.
Description of X‐linkage pedigrees
Authors: Risch Neil
Published: June 2005

A description of the pedigrees informative for linkage with X‐chromosome markers used as part of the affective disorders workshop is given.
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

The 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

Simulation 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

Linkage 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

The 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

We 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

Implicit 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

The 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

This 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

A 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

Extensions 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

Unlike 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

Children 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

The 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

Linkage 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.
Association of a Pvull RFLP at the lipoprotein lipase locus with fasting insulin levels in Hispanic men
Authors: Cole S. A. , Aston C. E. , Hamman R. F. , Ferrell R. E.
Published: June 2005

We present results from an association study between RFLPs in the lipoprotein lipase (LPL) gene and lipid and insulin levels. The study population consisted of 102 Hispanic men and 97 Hispanic women. The subjects were genotyped for two previously reported RFLPs detected with the restriction enzymes HindIII and PvuII. The frequencies of the RFLPs in the Hispanic population are similar to those seen in other Caucasian populations. Strong linkage disequilibrium was detected between the sites in Hispanics. Genotypes were used separately in analyses of variance with fasting serum triglycerides, total cholesterol, high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, HDL2/HDL3‐cholesterol, and insulin levels, as well as two measures of adiposity: waist‐hip ratio and body mass index. Men and women were analyzed separately. Mean fasting insulin levels of the LPL PvuII genotypes were significantly different from each other in Hispanic men. The mean fasting insulin level of men who were homozygous for the presence of the PvuII site (+/+) was 9.20 ± 0.24 μunits/ml, men who were heterozygous had a mean level of 10.54 ± 0.20 μunits/ml, and men who were homozygous for the absence of the site (‐/‐) had a mean of 12.91 ± 0.30 μunits/ml. This effect was not seen in Hispanic women. These results suggest that the regulation of LPL by insulin may be different in Hispanics with different LPL PvuII genotypes. © 1993 Wiley‐Liss, Inc.