bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological and cultural sources of familial resemblance in plasma lipids: A comparison between North America and Israel—the lipid research clinics program
Authors: Bucher K. D. , Friedlander Y. , Kaplan E. B. , Namboodiri K. K. , Kark J. D. , Eisenberg S. , Stein Y. , Rifkind B. M. , Rao D. C.
Published: June 2005

Heterogeneity in determinants of familial resemblance of lipid and lipoprotein levels between populations in North America and Israel was investigated using path analysis. A common protocol, identical measurement techniques, and the same statistical procedures were used in the two samples. Both genetic (h2) and cultural (c2) determinants of inheritance were significant for all lipid variables in the two studies. Genetic and cultural heritability of total cholesterol (h2 = 0.61, c2 = 0.02), low‐density lipoprotein cholesterol (h2 = 0.59, c2 = 0.02), and high‐density lipoprotein cholesterol (h2 = 0.55, c2 = 0.06) did not differ significantly between North America and Israel, while there was a significant difference for triglyceride (h2 = 0.41, c2 = 0.07 in North America; h2 = 0.61, c2 = 0.05 in Israel). Secondary parameters of the path model describing intrafamilial environmental relationships differed between the two countries. In particular, there was a higher correlation between marital environments in Israel for all traits except triglyceride, and a larger effect of father's environment on offspring's environment in Israel for all traits. Within both populations, variation of plasma lipids and lipoproteins was mostly explained by genetic factors and random unmeasured environmental factors. The contribution of common family environment was found to be small, though statistically significant. This is probably due to homogeneity of the distribution of familian environmental determinants within both countries.
Segregation analysis of leprosy in families of northern Thailand
Authors: Wagener Diane K. , Schauf Victoria , Nelson Kenrad E. , Scollard David , Brown Arthur , Smith Trevor , Borecki Ingrid B.
Published: June 2005

Sixty‐three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum‐likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.
Segregation and linkage analysis of nine Utah breast cancer pedigrees
Authors: Bishop D.T , Cannon‐Albright L. , McLellan T. , Gardner EJ , Skolnick MH , Rao D. C.
Published: June 2005

The analysis of nine Utah families that were ascertained for clusters of breast cancer cases is reported. Segregation analysis of an inherited susceptibility to breast cancer shows two distinct maximum likelihood solutions that have almost equal likelihood. One model indicates that most females had zero risk for breast cancer, but 10% of the female population had risks much greater than the Utah age‐specific incidence rates. The other model indicates that most females have a risk defined by the Utah rates for breast cancer, but a rare dominant gene is segregating for increased susceptibility to breast cancer. Our analysis shows that linkage results under the two models are consistent in sign but not in magnitude. No evidence for linkage was found with the 14 marker loci examined. In addition to demonstrating distortion of linkage results from ignoring sporadic cases, this analysis shows the inherent difficulty of obtaining parameter estimates for segregation analysis when families are ascertained from a cluster of cases.
Alcohol effects on the percentage of beta waves in the electroencephalograms of twins
Authors: Christian Joe C. , Li Ting‐Kai , Norton James A. , Propping Peter , Yu Pao‐Lo , Rao D. C.
Published: June 2005

Electroencephalogram (EEG) recordings were made from 26 pairs of monozygotic (MZ) and 26 pairs of dizygotic (DZ) adult male twins, before and after alcohol ingestion. After a baseline EEG and a light breakfast, 1.2 ml/kg of ethanol was given orally over 15 min and the EEG repeated four times at hourly intervals. Alcohol caused a significant drop in the percentage of beta waves (14–30 cycles/sec) during the 1st hr. For the percentage of beta waves in 38 pairs of twins with complete data, MZ twin beta‐wave intraclass correlations (RMZ) ranged between 0.85 and 0.91 before and after alcohol, but the DZ intraclass correlations (RDZ) started at 0.54 and fell to 0.05 at 2 hr after alcohol before recovering to baseline levels. These correlations resulted in heritability estimates [2(RMZ‐RDZ)] of 0.68 at baseline and 1.73 at 2 hr. A heritability of 1.43 was found for the 1st hr drop in percentage of beta waves (RMZ = 0.78, RDZ = 0.06). These unrealistically high heritabilities, due to RDZ's approaching 0.0, suggest a failure of assumptions in the linear twin model that was used. Also, these findings are similar to, but more exaggerated than, findings in resting EEG's and visually evoked EEG potentials of twins and are compatible with the influence of gene interactions.
Effect of maternal and infant covariates on sibship correlation in birth weight
Authors: Beaty TH , Yang P. , Muñoz A. , Khoury MJ , Rao D. C.
Published: June 2005

Birth weight on 12,644 singleton infants from 6,196 sibships born in Maryland between 1980 and 1984 were used to estimate the effects of nine maternal and infant covariates on the sibship correlation in birth weight. Assuming a homogeneous correlation across all families, the estimated intraclass correlation was 0.4664 (± 0.0099). This high sibship correlation makes it possible to predict, with reasonable accuracy, the birth weight of a child given information on previous sibs, as well as covariates on the mother and/or infant pertinent to a given pregnancy. The reduction in variance associated with incorporating information on the nine covariates used here was approximately equal to that obtained by conditioning on a single previous sib. Testing for heterogeneity in correlation among different groups of families showed that a crude measure of parity (first live birth vs. other), time between births, mother's marital status, and maternal age at the birth of the last child significantly influenced the sibship correlation in birth weight.
Estimating genetic parameters of survival distributions: A multifactorial model
Authors: Meyer Joanne M. , Eaves Lindon J.
Published: June 2005

For a number of genetically influenced illnesses, age of onset is correlated between relatives. In some cases, age of onset also serves as an index of an individual's inherited liability to an illness. Typically, survival models for age of onset distributions do not allow for these effects. We have used the gamma distribution as the basis of a model which specifies genetic variability in age of onset. Specifically, we allow the hazard frequency parameter of the gamma distribution to be a monotonic function of an individual's inherited liability to an illness. Simulations under various gamma models indicate that age of onset correlations may be strikingly different from correlations in liability. Maximum likelihood estimation procedures were used to obtain parameter estimates from simulated data sets and to determine whether it is possible to discriminate between gamma processes of different order. The results for 1,000 pairs of twins (500 monozygotic and 500 dizygotic) gave parameter estimates that were fairly accurate but that decreased in precision as the order of the gamma process increased. We discuss the effect this may have on inferences made about age of onset.
Lifestyle and blood pressure levels in male twins in Utah
Authors: Slattery Martha L. , Bishop D. Timothy , French Thomas K. , Hunt Steven C. , Meikle A. Wayne , Williams Roger R. , Rao D. C.
Published: June 2005

Healthy male monozygotic (MZ) and dizygotic (DZ) twin pairs (MZ pairs = 77; DZ pairs = 88) were studied to assess the effect of dietary intake, physical activity, physical fitness, body mass index (BMI), sum of the triceps and subscapular skinfold measurements, alcohol and caffeine consumption, and smoking patterns on blood pressure. Data on physical activity, detailed dietary intake, medical history, and demographics were obtained from a questionnaire. A bicycle ergometer was used to estimate level of fitness; other medical information was ascertained from physical examination. After normalizing the study variables, intraclass correlations for BMI and the sum of the triceps and subscapular skinfold measurements were higher in MZ than in DZ twin pairs (BMI: MZ r = 0.76, DZ r = 0.48; skinfolds: MZ r = 0.73, DZ r = 0.28), as were VO2max(MZ r = 0.63, DZ r = 0.25) and post‐bike heart rate (MZ r = 0.69, DZ r = 0.19). Both systolic (SBP) and diastolic blood pressure (DBP) had high heritability estimates (SBP = 0.60, and DBP = 0.66). Using factor analysis, four major lifestyle factors were identified and categorized as: 1) dietary intake; 2) a factor heavily weighted by cigarette smoking, alcohol and caffeine consumption; 3) fatness; 4) physical activity and physical fitness. Adjustment for these factors did not alter heritability estimates for either SBP or DBP.
Twin study of genetic and environmental effects on lipid levels
Authors: O'Connell DL , Heller RF , Roberts DCK , Allen JR , Knapp JC , Steele PL , Silove D. , Vogler G. P. , Rao D. C.
Published: June 2005

A study of 106 pairs of monozygotic (MZ) and 94 pairs of dizygotic (DZ) twins tested the hypothesis that part of the previously described genetic influence on blood lipid levels can be ascribed to closer similarities among MZ than among DZ twin pairs in environmental factors that affect lipid levels. Participants were adult twin volunteers (age 17–66; 64 male and 136 female pairs) who were selected from the NH & MRC Twin Registry or were respondents to advertisements. They completed a 4‐day weighed food diary from which mean nutrient intake was derived. Information on lifestyle and demographic variables was obtained by questionnaire and a nonfasting blood sample was taken for measures of total, low‐density lipoprotein (LDL) cholesterol, and high‐density lipoprotein (HDL) cholesterol and the HDL2 and HDL3 subfractions. Height and weight were measured, and body mass index (BMI) was calculated (kg/m2). Estimates of the heritability of sex‐adjusted lipid levels were 0.72 for total cholesterol, 0.79 for HDL cholesterol, 0.69 for HDL2, 0.20 for HDL3, 1.06 for LDL cholesterol, and 0.44 for sex‐adjusted BMI. In all cases except for HDL3, genetic variance was statistically significant. After adjusting for the effects of environmental variables in three different ways, the estimates of heritability were somewhat lower for total cholesterol, HDL2, and BMI, and those for HDL cholesterol (borderline) and LDL cholesterol (definitely) remained statistically significant but were decreased. A genetic influence on HDL3 was not found. Adjusted heritability estimates obtained from one method of analysis were 0.35 for total cholesterol, 0.49 for HDL, 0.04 for HDL2, −0.34 for HDL3, 0.66 for LDL, and 0.32 for BMI. These results suggest that the assumptions made in the classical twin study approach are not appropriate when examining genetic effects on lipid levels or BMI, or indeed on any biological variable that may be more similar in MZ twins than in DZ twins. In these circumstances, more complex models may be needed to differentiate between genetic and environmental influences.
Assessing familial aggregation of congenital cardiovascular malformations in case‐control studies
Authors: Maestri Nancy E. , Beaty Terri H. , Liang Kung‐Yee , Boughman Joann A. , Ferencz Charlotte , Rao D. C.
Published: June 2005

Recent data indicate that the familial aggregation of congenital cardiovascular malformations (CCVM) varies with the type of defect in the index case. Using a logistic regression model that allows for dependence among family members, we calculated the risk of any CCVM to case relatives compared with relatives of controls. Data from 3,908 first‐degree relatives of 570 matched cases and controls identified from 1981 through 1985 by the Baltimore‐Washington Infant Study were used in the analyses. Overall risk for any CCVM in case relatives was increased four‐fold over that of control relatives. While relatives of cases with flow lesions (including right and left heart defects, as well as perimembranous ventricular septal defect [VSD]) had a five‐fold increase in risk, the risk to relatives of nonflow lesion cases did not differ significantly from the risk to relatives of controls. Sex, maternal age, miscarriage history in the mother, and birth order had no apparent effect on risk among siblings. However, there was an indication of increased risk in relatives of nonwhite cases with VSD compared to relatives of matched controls. However, with these data it was not possible to distinguish between environmental and genetic sources of this familial aggregation.
Partial linkage map of chromosome 13q in the region of the Wilson disease and retinoblastoma genes
Authors: Haines Jonathan L. , Ozelius Laurie , George‐Hyslop Peter St , Wexler Nancy S. , Gusella James F. , Conneally P. Michael , Vogler G. P.
Published: June 2005

Genetic linkage maps are useful tools for defining the location of disease genes. Previously published maps of human chromosome 13 have been incomplete and have had ambiguities of order in the vicinity of the Wilson disease (WND) and retinoblastoma (RBl) genes. We have defined a six‐locus map of this region using a large reference pedigree from Venezuela. Our map provides landmarks which will aid in the localization of WND, in determining the extent of deletions in retinoblastoma, and in the mapping of other marker loci.
The impact of varying diagnostic thresholds on affected sib pair linkage analysis
Authors: Kendler Kenneth S. , Vogler G. P.
Published: June 2005

For Mendelian disorders, it is usually simple to classify individuals as either affected or unaffected. By contrast, for “complex” phenotypes, the diagnostic boundary of the disorder is often uncertain. This paper explores the following question: to most efficiently detect linkage in such a complex phenotype by the affected sib pair method, where should the diagnostic threshold be drawn? The model assumes that the disorder is due to a generalized two‐allele single major locus (SML) where liability in each genotype is normally distributed. Evidence for linkage between the marker and disease loci is highly dependent on the location of the threshold. The relationship between the placement of the threshold and population linkage information (PLI) is Gaussian‐like. At high thresholds, linkage efficiency (LE) (or the amount of linkage information per affected sib pair) is high but PLI is low because the number of affected sib pairs is very small. At low thresholds, the number of affected sib pairs is high, but PLI is low because LE is very low. The model is applied to published SML parameters for schizophrenia, and maximal PLI is achieved at thresholds broader than those for schizophrenia alone.
HLA and insulin‐dependent diabetes: An overview
Authors: Svejgaard Arne , Ryder Lars P.
Published: June 2005

The present knowledge of the HLA system and its biological function is summarized as a basis for the subsequent discussion of the associations between this system and insulin‐dependent diabetes (IDDM) and some mechanisms that may explain them. Although the serologically detectable DR determinants are still the most handy markers, there is now increasing evidence from studies of restriction enzyme fragment length polymorphism (RFLP) in IDDM that DQ determinants may play a primary role in causing susceptibility and/or resistance to this disease. Thus, it is now evident that about 90% of DR4‐positive diabetics carry the DQw8 determinant present in only about 65% of DR4‐positive controls. Most recently, it has been claimed that an aspartic acid in position 57 of the DQBI (DQ‐beta‐1) chain confers resistance to IDDM. Although this may be true, it does not explain the disproportionate decrease of DR2 or the particularly high risk of DR3/4 heterozygotes, which is still good evidence that several HLA genes are involved. Because Class II antigens show the strongest associations, the most plausible hypothesis about the mechanism(s) involves specific presentation of as yet unknown antigenic peptides to T‐helper lymphocytes, which may induce the formation of both anti‐islet cell antibodies and T‐cytotoxic lymphocytes capable of destroying beta cells. However, T‐suppressor lymphocytes also may be involved. If this hypothesis is correct, the most urgent task is to define the antigenic peptides in question, whether they are environmental (e.g., viral) or autologous.
Coxsackie B virus assays in IDDM families: The GAW5 data on antibody prevalence
Authors: Yoon J. W. , Kim K. W. , Kim H. M. , Pak C. Y. , Kim Y. W. , McArthur R. G.
Published: June 2005

There is evidence that infection by Coxsackie viruses can serve as an environmental “trigger” for insulin‐dependent diabetes mellitus (IDDM). This background information is summarized briefly, and the data in the IDDM component of Genetic Analysis Workshop 5 (GAW5) concerning serum antibodies to Coxsackie B viruses are described.
Autoantibodies to pancreatic islet cells and insulin in IDDM families: The GAW5 data
Authors: Maclaren Noel K. , Riley William J. , McCulloch David K. , Palmer Jerry P.
Published: June 2005

Antibodies to pancreatic islet cells and insulin were studied in the Genetic Analysis Workshop 5 (GAW5) families, as indicators of an autoimmune component of pathogenesis. The rationale for these studies is summarized briefly, and references to the laboratory methods used are provided.
The insulin gene and susceptibility to IDDM
Authors: Cox Nancy J. , Spielman Richard S.
Published: June 2005

The association between insulin‐dependent diabetes mellitus (IDDM) and an allele of a restriction fragment length polymorphism (RFLP) 5′ to the coding region of the insulin gene has raised the possibility that variation in the vicinity of the insulin gene confers susceptibility to IDDM. To test this hypothesis, the distribution of insulin gene sharing in affected sib pairs (ASPs) from the Genetic Analysis Workshop 5 (GAW5) families has been compared with that expected on the basis of random assortment. There is no deviation from random expectation in insulin gene sharing among 95 ASPs from families fully informative for the insulin gene. This is also true when insulin gene sharing is conditioned on HLA sharing, on the particular HLA DR types in ASPs, or on the parents' insulin allele classes. These results thus provide no evidence that variation at or near the insulin gene confers susceptibility to IDDM. However, we also used computer simulation to investigate how the insulin gene region could contribute susceptibility to IDDM without yielding evidence for distortion in insulin gene sharing in a sample comparable to that of GAW5. We found that various levels of insulin gene involvement in IDDM could generate a population association between the insulin gene RFLP and IDDM comparable to that reported in the literature, without producing significant distortion in insulin gene sharing of ASPs.
Linkage studies of HLA and insulin gene restriction fragment length polymorphisms in families with IDDM
Authors: Donald J. A. , Barendse W. , Cooper D. W.
Published: June 2005

Linkage analysis of HLA DR antigen as well as DR and DQ restriction fragment length polymorphism (RFLP) data using the LIPED computer program and various three‐allele disease locus models showed very close linkage to an insulindependent diabetes mellitus (IDDM)‐susceptibility locus. RFLP data alone were equal or superior to conventional HLA antigen typing in the linkage analysis. Insulin gene restriction fragment data were analyzed for evidence of either a susceptibility locus linked to the insulin gene or an effect of alleles at the insulin locus on the HLA‐linked susceptibility gene. No evidence was found of any effect of the insulin gene, and it is suggested that alternative explanations of the reported population associations between the insulin gene and IDDM should be considered.
NIMH collaborative program on the psychobiology of depression: Clinical
Authors: Rice John , Andreasen Nancy C. , Coryell William , Endicott Jean , Fawcett Jan , Hirschfeld Robert M. A. , Keller Martin B. , Klerman Gerald L. , Lavori Philip , Reich Theodore , Scheftner William A.
Published: June 2005

As part of the National Institute of Mental Health Collaborative Program of Depression study, data were collected on 2, 225 first‐degree relatives of 612 probands. A subset consisting of 187 families of bipolar patients was made available to participants of Genetic Analysis Workwhop 5 (GAW5). A description of these data, including sample sizes, diagnoses, and a summary of published analyses, is given.
Linkage analysis with cohort effects: An application to X‐linkage
Authors: Van Eerdewegh Paul
Published: June 2005

The LIPED program has been modified to incorporate cohort effects in a linkage analysis. Very significant positive lod scores are obtained between bipolar affective disorder and both the deutan and protan markers on the X‐chromosome. Lod score methods are shown to be sensitive to the specification of the age onset distributions and the parameters of the model of transmission.
Linkage analysis with inbreeding
Authors: Van Eerdewegh Paul
Published: June 2005

For computational reasons, linkage analysis of highly inbred pedigrees is often performed under the assumption that spouse pairs are genetically unrelated. A formulation of the likelihood of a pedigree which takes into account all of the genealogical information Ω, for an arbitrary relationship between a pair of spouses, is proposed. Lod scores at a recombination fraction of 0 for an inbred three‐member nuclear family are presented.
Utility of the affected sib pair method to detect linkage of a sex‐linked dominant disease with a sex‐linked recessive trait
Authors: Chakraborty Ranajit
Published: June 2005

Use of affected sib‐pairs for linkage determination of a sex‐linked dominant disease with a recessive X‐chromosome marker will require extremely large sample sizes, particularly when the marker is marginally polymorphic. In addition, this method should not be used without caution on data collected for a traditional LOD score analysis, without considering the parental mating types involved in the informative families. Nevertheless, ascertainment adjustment and correction for dependence of multiple pairs of affected sib‐pairs in families suggests that this method provides linkage inference concordant with that of the traditional LOD score analysis.
Affective disorder not linked to HLA
Authors: Price R. Arlen
Published: June 2005

These analyses focused on the relationship of affective disorders to HLA. The sample of 86 previously unpublished families from Ontario and 10 unpublished pedigrees from Newfoundland, as well as the original Weitkamp et al. [1981] sample of 20 families, the samples provided by NIMH [Goldin et al., 1982] (18 families), and Egeland et al. [1987] (2 large pedigrees), were examined using sib pair methods as well as standard linkage analysis of the full pedigrees. A variety of genetic models were examined. There was no evidence for linkage from any of the samples based on either analytic approach or for any genetic model. Groups of sibling pairs concordant for affective illness, concordant for being well, or discordant for affective illness did not differ in the proportion of genes identical by descent. No group differed significantly from 50%. From the analysis of full pedigrees, linkage to HLA could be excluded to a distance of approximately 20 to 25 centimorgans. There was no evidence for linkage heterogeneity. These results argue against linkage of affective disorder to HLA.
Nonrandom sampling in genetic epidemiology: An implementation of the Hanis‐Chakraborty method for multifactorial analysis
Authors: Rao D. C. , Wette R. , Chakraborty Ranajit
Published: June 2005

The method of Hanis and Chakraborty: [Statistics in Medicine 6:629–646, 1987] is known to yield unbiased estimates of familial correlations from family data ascertained according to just about any method of nonrandom sampling. For multifactorial analysis of such family data, the method is implemented here so as to provide a unique solution, handle variable sibship sizes, and provide likelihood ratio tests of hypotheses. Simulation results are presented to illustrate the utility of the proposed implementation.
Linkage detection tests under heterogeneity
Authors: Risch Neil , Rao D. C.
Published: June 2005

A two‐parameter (admixture) test (Lod2) for the detection of linkage which allows for heterogeneity is described. Lod score values for this test which lead to comparable type 1 error probabilities as the conventional (homogeneous) single‐parameter lod score test (Lod1) are derived. For example, a Lod2 value of 3.70 corresponds to the conventional lod score (Lod1) value of 3.0. In terms of power to detect linkage, the Lod2 test is advantageous only for moderate to large pedigrees (autosomal dominant inheritance with high penetrance) and when the proportion of linked families is low (less than 40%). Otherwise, there appears to be no serious disadvantage in using the conventional Lod1 test when heterogeneity is present.
The distribution of debrisoquine metabolic phenotypes and implications for the suggested association with lung cancer risk
Authors: Caporaso Neil , Pickle Linda Williams , Bale Sherri , Ayesh Riad , Hetzel Martin , Idle Jeffrey , Rao D. C.
Published: June 2005

Debrisoquine hydroxylation exhibits wide inter‐individual variation in Caucasian populations. After similar doses of the drug, extensive metabolizers excrete up to several hundred times more of the urinary metabolite 4‐hydroxy‐debrisoquine than do poor metabolizers. The phenotypes have traditionally been defined by the metabolic ratio (MR), or the molar ratio of debrisoquine to its chief metabolite recovered in an aliquot of an eight hour urine sample, after a test dose of the drug. Deficient metabolism is inherited as an autosomal recessive condition.

We have reanalyzed previously published data from a study of lung cancer patients and controls using a computerized optimization method to more accurately estimate the parameters describing the three phenotypic distributions. Using these new distributions to categorize controls, we show that Hardy‐Weinberg conditions are now fulfilled. When the newly defined phenotype parameters are employed to assign the phenotypes of cases and controls, a highly significant difference in phenotype distribution between cases and controls is still observed. This result supports the hypothesis that the debrisoquine metabolic phenotype may be associated with lung cancer susceptibility.
Equivalence of the mixed and regressive models for genetic analysis. I. Continuous traits
Authors: Demenais Florence M. , Bonney George E. , Rao D. C.
Published: June 2005

The mixed model of segregation analysis specifies major gene effects and partitions the residual variance into polygenic and environmental components. The model explains familial correlations essentially in terms of genetic causation. The regressive model, on the other hand, is constructed by successively conditioning on ancestral phenotypes and major genes. Familial patterns of dependence are described in terms of correlations without necessarily introducing a particular scheme of causal relationship. These two approaches are compared both theoretically and numerically through computer simulations for the case of continuous traits on nuclear families. The class D regressive model, which is characterized by equal sib—sib correlations, is mathematically and numerically equivalent to the mixed model. The simpler class A regressive model, which is also characterized by equal sib—sib correlations determined in this case by the common parentage, provides good estimates of the mixed model parameters: major gene parameters and residual polygenic heritability, derived from the parent—offspring correlation. However, in the absence of a major gene, the restriction imposed by the class A model on the sibling correlation can affect the conclusions of segregation analysis: False inference of a major gene was observed in two out of ten replicates. Our simulations also indicate that the mixed model allowing for different heritabilities in adults and children leads to correct estimates of the major gene parameters and residual familial correlations (parent—offspring and sib—sib) as specified by the class A model. For all the models studied, major gene effects, when present, are correctly detected and estimated.
Complex segregation analysis for a three‐allele locus: Experience from an analysis of acid phosphatase activity
Authors: Iselius L. , Evans D. A. P. , Eze L. C. , Tweedie M. C. K. , Bullen M. F. , Wren P. J. J. , Rao D. C.
Published: June 2005

A complex segregation analysis of acid phosphatase activity in 50 British families showed that the essential features of the acid phosphatase polymorphism, i.e., a major gene with three alleles, is retrieved by using the biallelic mixed model. The estimates of gene frequency and displacement obtained from segregation analysis were in agreement with those obtained from electrophoretic studies. In addition, there was evidence for a multifactorial component.
Test of genetic heterogeneity of cleft lip with or without cleft palate as related to race and severity
Authors: Chung C. S. , Beechert A. M. , Lew R. E. , Vogler G. P. , Rao D. C.
Published: June 2005

The question of possible heterogeneity among population groups and phenotypic groups on the role of major gene in the etiology of cleft lip with or without cleft palate [CL(P)] was examined using the uniformly collected data in Hawaii. Complex segregation analysis was used to analyze patterns of family resemblance under the mixed model incorporating the effects of major gene and multifactorial inheritance. Analysis of the entire data showed superior fit of the mixed model including the effects of both major gene and multifactorial inheritance over the model of major gene alone or multifactorial inheritance alone. No significant heterogeneity could be detected between the high‐incidence group (Oriental or Japanese) and the low‐incidence group (non‐Oriental) in the underlying general model, although higher heritability was observed in general. When families were classified into “severe” and “mild” phenotypes based on cleft lip vs. cleft lip and palate or unilateral vs. bilateral cleft in the proband, no significant differences could be detected between the two types in the underlying genetic model.
Commingling and segregation analyses: Comparison of results from a simulation study of a quantitative trait
Authors: Kwon Jennifer M. , Boehnke Michael , Burns Trudy L. , Moll Patricia P. , Vogler G. P. , Rao D. C.
Published: June 2005

Commingling analysis is commonly used to provide preliminary evidence for a single genetic locus with a major effect on the quantitative trait of interest. In this paper, the effectiveness of commingling analysis as a screening technique to identify samples for segregation analysis is assessed by applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual‐specific environmental effect. Under the circumstances simulated here, there is evidence for a single locus from segregation analysis but not from commingling analysis in at least 20% of the samples. No more than 2% of the samples provided evidence for commingling but not for segregation of a single locus. Comparisons of the samples that give evidence for both commingling and segregation, evidence for one but not the other, and no evidence for either show that evidence for commingling depends on the distributional characteristics of the trait in the sample, while support for the single locus from segregation analysis depends on both the distributional characteristics as well as the transmission of the rarer allele from parents to offspring. Since lack of commingling does not rule out the existence of a single locus in the realistic situations considered here, commingling analysis has limited usefulness as a screening technique for the presence for a single locus. In contrast, evidence for commingling does suggest the possibility that a single locus has a major effect on the trait and commingling analysis can provide guidance in the choice of initial parameter estimates for segregation analysis.
Linkage disequilibrium between DNA markers at the low‐density lipoprotein receptor gene
Authors: Hegele Robert A. , Plaetke Rosemarie , Lalouel Jean‐Marc , Vogler G. P. , Rao D. C.
Published: June 2005

We determined pairwise linkage disequilibria between 12 restriction fragment length polymorphism (RFLP) markers at or near the low‐density lipoprotein receptor (LDLR) locus on chromosome 19p13.2‐13.1 in 92 unrelated individuals. Of these 12 RFLPs, two were newly identified under a cosmid‐based strategy designed to screen for RFLPs. We estimated linkage disequilibrium by determining three different measurements: D (the maximum likelihood estimate of linkage disequilibrium), D' (Lewontin's normalized estimate of D), and r (an index of gametic correlation). When r was used as the estimate of linkage disequilibrium, five of the 66 comparisons were significant according to a level of significance adjusted by the Bonferroni‐Holm correction. Only four pairs of RFLPs within a 100 kb region that included the LDLR gene itself were in significant linkage disequilibrium. Although we were able to detect strong linkage disequilibrium between some pairs of RFLPs in this sample, most RFLPs at the LDLR locus were not in strong linkage disequilibrium despite their physical proximity.
A family study of panic disorder: Reanalysis using a regressive logistic model that incorporates a sibship environment
Authors: Hopper John L. , Judd Fiona K. , Derrick Peter L. , Macaskill Greg T. , Burrows Graham D. , Rao D. C.
Published: June 2005

Previous analysis of affection status in parents and siblings of 117 probands with panic disorder by a log‐linear model for binary pedigree data found a common concordance across biological first‐degree relatives and no spouse association [Hopper JL, Judd FK, Derrick PL, Burrows GD: Genet Epidemiol 4:33–41, 1987]. In this paper the data were reanalyzed using a regressive logistic model that modelled both vertical transmission and a shared sibship environment. Ascertainment correction was made by a) an “ascertainment assumption‐free” procedure, following Ewens and Shute [Theor Pop Biol 30:388–412, 1986] and compared with b) complete ascertainment and c) single ascertainment. Under every scheme there was evidence for vertical transmission from parents to offspring. Inclusion of a sibship environment gave an improved fit, suggesting that vertical transmission alone may not be sufficient to explain the familial aggregation observed in these families. The effects of an affected parent, of the postulated environmental factor (present for all siblings if it was present for one sibling), and of the prevalence of the rare environmental factor were estimated and found to be roughly similar under the different schemes. Model predictions of lifetime prevalence were consistent with other population‐based studies. Under the same assumption‐free method, standard errors approximately doubled and computation time increased compared with the other ascertainment schemes that made specific, although not necessarily correct, assumptions. The regressive logistic model used less computation time and gave greater insight into the pattern of familial aggregation than did the previous modelling.
Familial resemblance of plasma apolipoprotein B: The Nancy study
Authors: Tiret Laurence , Steinmetz Josianne , Herbeth Bernard , Visvikis Sophia , Rakotovao Roger , Ducimetiere Pierre , Cambien Francois , Borecki I. B. , Rao D. C.
Published: June 2005

The familial resemblance of plasma apolipoprotein B (apo b) was investigated in a sample of 102 families including 419 members who volunteered for a free health checkup in the Preventive Center of Vandoeuvre‐lès‐Nancy, France. The mean levels (±SD) of apo B were 141.0 (±32.6), 121.8 (±27.7), and 98.6 (±22.6) mg/dl in fathers, mothers, and offspring, respectively. The familial correlations were 0.04, 0.13, 0.21 (P < .01), and 0.47 (P < .001) between spouses, father‐offspring, mother‐offspring, and siblings, respectively, after adjustment on age, body mass index, and sex. A genetic analysis was performed using the approach proposed by Bonney, which indicated that a recessive and a dominant major‐locus model appeared nearly equally supported by the data. Under the recessive model, the frequency q of the most common allele was estimated as 0.825, with a mean difference of 60.4 mg/dl between high and low homozygotes. Under the dominant model, q was estimated as 0.875, with a mean increase of 34.2 mg/dl in heterozygotes and high homozygotes. However, the hypothesis of Mendelian transmission and the environmental hypothesis could not be formally tested because of great numeric difficulties encountered in the estimation of the three transmission probabilities. Given these analytical restrictions, we cannot conclude in favor of a major locus influencing apo B level in our population, even though the evidence is suggestive. The genetic heterogeneity underlying the familial aggregation of apo B level, suggested by several recent publications, might explain the difficulty in discerning a single major locus in a population sample of small nuclear families, not ascertained through patients enriching the sample in high values of apo B. These findings call into question the relevance of the approach through “healthy” populations in the search for major loci influencing biological traits.
Power of the linkage test for a heterogeneous disorder due to two independent inherited causes: A simulation study
Authors: Martinez Maria , Goldin Lynn R. , Rao D. C.
Published: June 2005

We have conducted a simulation study in small pedigrees to investigate the power to detect linkage and heterogeneity for a disorder due to either one of two independent disease loci. We have considered a highly polymorphic marker locus (PIC = 70%) linked to one disease locus and unlinked to the second. The power to detect linkage has been examined by using the admixture test. We have varied the mode of transmission of each disease locus, the ascertainment of families and the proportion of cases in the population due to the linked disease locus. Generally, for the multiplex ascertainments we have considered, the power to detect linkage is greater when the linked disease locus has a high penetrance, when the unlinked disease locus has a low penetrance, and when pedigrees with multiple affected are selected. When selecting families with multiple affected, the rate of “mixed” families (i.e., those segregating for both disease loci) increases. However, for the pedigree structure we have considered, the power of the linkage test is more affected by a decrease in the rate of “linked” families than by an increase in the rate of “mixed” families. Finally, the present study shows that detection of linkage in presence of heterogeneity is feasible with a realistic sample size of small pedigrees as long as the linked disease locus accounts for more than 25% of the cases.
Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis
Authors: Weeks Daniel E. , Lehner Thomas , Squires‐Wheeler Elizabeth , Kaufmann Charles , Ott Jurg , Rao D. C.
Published: June 2005

A computer‐simulation method is presented for determining and correcting for the effect of maximizing the lod score over disease definitions, penetrance values, and perhaps other model parameters. The method consists of simulating the complete analysis using marker genotypes randomly generated under the assumption of free recombination. It is applicable as a “post‐treatment” to linkage analyses of any trait with an uncertain mode of inheritance and/or disease definition. When the method is applied to a linkage analysis of schizophrenia versus chromosome 5 markers, we find that, in this specific case, the P‐value associated with a maximum lod score of 3 is equal to 0.0003. We also find that a lod score of 3.0 should be “deflated” by approximately 0.3 to 1 units, and, by tentative extrapolation, the observed lod score of 6.5 should be “deflated” by 0.7 to 1.5 units.
Familial factors associated with malignant gliomas
Authors: Wrensch Margaret R. , Barger Geoffrey R. , Rao D. C.
Published: June 2005

Family histories of male patients with histologically confirmed malignant gliomas were compared to family histories of controls (wives). Included were 77 case families with 892 relatives and 77 control families with 719 relatives. Cases had significantly more siblings than controls (P = 0.02), although cases were not preferentially the oldest or the youngest sibs. Odds ratios of two or more were found for mental retardation, Parkinson's disease, and meningitis for the relatives of cases versus controls, but none were statistically significant. The excesses of Parkinson's disease and meningitis were explained by the family of one particularly interesting case containing three relatives with meningitis and two relatives with Parkinson's disease. Noteworthy age‐adjusted odds ratios for cancer among relatives of cases compared to relatives of controls were 1.6 (95% confidence interval (CI) = 1.0–2.3) for cancer of any site, 2.4 (95% CI = 0.8–6.1) for breast cancer, and 4.0 (95% CI = 0.6–10.7) for lung cancer. Only the odds ratio for cancer of any site was statistically significant. Overall, 6 of 77 (8%) of cases came from families that included two or more relatives with breast or lung cancer in addition to the proband with malignant glioma. These three cancer sites may form familial clusters worthy of further evaluation in future studies by pedigree and genetic linkage analyses.
Sib‐pair linkage tests for disease susceptibility loci: Common tests vs. the asymptotically most powerful test
Authors: Schaid Daniel J. , Nick Todd G. , Rao D. C.
Published: June 2005

Several statistical tests for linkage between a disease susceptibility locus and a marker locus for sib‐pair data are examined analytically. Two common statistics, a test based on the mean number of marker alleles shared identical by descent by sib‐pairs, and a test based on the proportion of sib‐pairs sharing exactly two marker alleles, are shown to be special cases of a more general statistic. We use this more general statistic to derive the asymptotically most powerful statistic for a given genetic alternative hypothesis, and then compare this statistic with the “mean” statistic and the “proportion” statistic. Results indicate that the “mean” statistic generally compares well with the most powerful statistic. However, in some instances the “mean” statistic may lose power, relative to the most powerful. To guard against this, a new statistic (the maximum of the “mean” and “proportions” statistics) is considered and its asymptotic distribution is derived. Results indicate that this new statistic performs well.
Estimating familial effects on age at onset and liability to schizophrenia. I. Results of a large sample family study
Authors: Kendler Kenneth S. , MacLean Charles J. , Rao D. C.
Published: June 2005

Previous analyses of age at onset in schizophrenia, which is highly variable and appears to be influenced by familial factors, have neglected to consider either (1) the impact of censoring on correlations in age at onset in affected relatives or (2) the impact of correlated ages at onset on the relationship between age at onset in the proband and risk in relatives. In this report, using methods outlined in the companion paper [MacLean et al., Genet Epidemiol 7:419–426, 1990] we examine these questions in the large family data set of schizophrenia collected by Lindelius [Acta Psychiat Scand (Suppl) 216:1–125, 1970]. Ages at onset are positively correlated in pairs of affected relatives (parent–offspring ≅ siblings > nieces/nephews) and these correlations are substantially higher after correction for censoring. Early age at onset is associated with higher risk of illness in siblings and nieces/nephews but not in children. These results are consistent with the hypothesis that age at onset in schizophrenia is influenced by familial factors which are probably genetic and which are mostly unrelated to factors influencing disease liability.
Genetic epidemiology of childhood brain tumors
Authors: Bondy Melissa L. , Lustbader Edward D. , Buffler Patricia A. , Schull William J. , Hardy Robert J. , Strong Louise C. , Vogler G. P.
Published: June 2005

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age‐, race‐, sex‐, and calendar‐year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis—NF‐1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li–Fraumeni cancer family syndrome.