bluuebunny/crossref_metadata_2025 huggingface dataset:
HLA and down syndrome (DS): Parents at the origin of the nondisjunction share no more HLA‐A and ‐B antigens with their DS child than controls
Authors: Stoll C. , Alembik Y. , Armbruster N. , Tongio MM , Mayer S. , Rao D. C.
Published: June 2005

Fifty couples and their children with Down syndrome (D.S.) were typed for HLA‐A and HLA‐B antigens and compared to 50 control families and 464 blood donors. The parental origin of the extra chromosome 21 was determined by cytogenetic methods. All individuals were caucasians and there was no history of consanguinity. No excessive HLA sharing was present in D.S. parents. The mothers of D.S. shared no more HLA antigens with their D.S. children than the control mothers with their normal children (14% vs. 18%). Thirteen of the fifty pairs (26%) (parent in whom the nondisjunction occurred and D.S. child) shared three HLA antigens at the A and/or B locus. This was not significantly higher than the proportion in the control group (12/50 or 24%). These data suggest that it is not the sharing of HLA‐A and HLA‐B antigens between the parents or between the parent who was the origin of the nondisjunction and the D.S. child that is related either to the occurrence of trisomy 21 zygotes or to prenatal survival of affected embryos and fetuses.
Some effects of selection strategies on linkage analysis
Authors: Cox Nancy J. , Hodge Susan E. , Marazita Mary L. , Spence M. Anne , Kidd Kenneth K. , Rao D. C.
Published: June 2005

A study was designed to address the relative merits of different sampling strategies for detecting linkage. Genotypes of pedigree members were generated by the use of a single genetic model, and the pedigrees were subdivided into dominant‐appearing, recessive‐appearing, and “interesting” subsets. An investigator blind to how the data had been generated applied two different selection rules to determine which individuals in each pedigree would be “typed” for linkage analysis. Linkage analyses were then conducted on these pedigree subsets, as well as on the combined data, by the use of three autosomal dominant models, three autosomal recessive models, and the generating (i.e., “true”) model. Results suggest (1) that linkage is likely to be detected even in the absence of knowledge of the mode of transmission, if a range of models can be examined; (2) that false evidence for heterogeneity will not necessarily result when pedigrees are selected according to apparent mode of transmission for analysis; (3) that recessive‐appearing pedigrees (i.e., those with multiplex sibships) may be particularly useful for detecting linkage; and (4) that including information on unaffected second‐degree relatives adds little to linkage studies of affected individuals and their first‐degree relatives.
Genetic factors influencing apolipoprotein AI and AII levels in a kindred with premature coronary heart disease
Authors: Borecki Ingrid B. , Laskarzewski Peter , Rao DC , Williams Roger R.
Published: June 2005

A single 51‐member kindred, ascertained on the basis of a normotriglyceridemic proband with depressed high‐density lipoprotein cholesterol (HDL‐C) and myocardial infarctions at ages 40 and 42, was studied with respect to quantitative variation in HDL‐C and apolipoprotein (apo) AI and AII levels. The results of bivariate segregation analysis suggest that the etiology of depressed HDL‐C involves one or possibly two major loci: one has a pleiotropic effect on apo AI and apo AII levels and, possibly another one that affects apo AI levels. Both the major loci were characterized as having a dominant allele leading to depression of the respective trait(s). In addition, analysis of the cosegregation of HDL‐C and apo AI levels gave evidence of residual nonfamilial factors common to both traits, leading to a positive covariance between them. This could reflect the role of apo AI in the transformation of nascent HDL‐C particles into mature ones via its cofactor activity to lecithin cholesterol acyltransferase. The proposed two‐locus model represents one possible etiology for the heterogeneous disorder of hypoal‐phalipoproteinemia. This analysis of a single pedigree does not completely define the genetic mechanism, but it does illustrate a useful new analytic approach.
Significant association of acute lymphoblastic leukemia with HLA‐Cw7
Authors: Müller C.A , Hasmann R. , Grosse‐Wilde H. , Vögeler U. , Bei‐Jun Chen , Dopfer R. , Waller HD , Lalouel J.‐M.
Published: June 2005

Frequencies of all defined HLA‐A, ‐B, ‐C (‐DR) antigens were determined in 142 (59) Germans suffering from acute lymphoblastic leukemia (ALL) with differentiation of immunologically defined or age‐related subgroups of the disease. A highly significant rise of the HLA‐C locus antigen Cw7 was found in ALL patients, particularly those over the age of 11 in comparison with local German and Caucasian controls of the Ninth Int. Histocompatibility Workshop (WS). Only slight differences of HLA‐Cw7 frequencies were observed within the four immunologically defined ALL subtypes of all or age‐related patient groups. HLA‐A, ‐B, or ‐DR antigens, as well as HLA‐ABC three‐locus haplotypes were similarly distributed in patients and their local or Caucasian controls. The results indicate HLA‐linked genetic factors conferring susceptibility to ALL in adults, particularly those presenting with B‐, T‐, and Null‐ALL.
Restriction fragment polymorphisms of the HLA‐DR, HLA‐DQ, and insulin gene regions in IDDM: The GAW5 data
Authors: Cox N. J. , Gogolin K. J. , Horvath V. J. , Barker D. F. , Wright E. , Tran T. , Skolnick M. H. , Boehm B. O. , Fehsel K. , Bertrams J. , Hodge T. W. , Acton R. T. , McGill J. , Elbein S. C. , Permutt M. A. , de Préval C. , Avoustin P. , Cambon‐Thomsen A. , Robinson D. M. , Holbeck S. L. , Nepom G. T. , Schneider P. M. , Rittner C. , Toyoda H. , Rotter J. I. , Spielman R.
Published: June 2005

The primary aim of the insulin‐dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5) was to collect and analyze new data on DNA polymorphisms closely linked to the HLA‐D region and the insulin gene. The probes and restriction enzymes described here were used by all ten participating labs, and the data from Southern blotting were interpreted and reported according to conventions developed for the Workshop. These DNA data on members of 94 families with two or more IDDM sibs constitute the largest such sample available. The data were used in most of the analyses presented at the Workshop meeting, and are available on request.
Immunoglobulin allotyping (Gm, Km) of GAW5 families
Authors: Field L. Leigh , Dugoujon Jean‐Michel
Published: June 2005

The following Gm and Km immunoglobulin allotypes were determined on the Genetic Analysis Workshop 5 insulin‐dependent diabetes mellitus (GAW5 IDDM) families: Glm (1,2,3,17), G2m (23), G3m (5,10,11,13,14,21,28) and Km (1,3). Since the allotype G2m (23) has been rarely studied, due to paucity of typing reagents, it was of interest to compare the frequency of the halotype encoding this allotype in parents of North American GAW5 IDDM families with the frequency found in a previous investigation of healthy North Americans. Results indicated very similar frequencies of Gm haplotypes in the two groups.
Charateristics of a multiplex IDDM sample: Unexplained differences with other samples
Authors: Falk Catherine T.
Published: June 2005

Characteristics of a multiplex sample of families with insulin‐dependent diabetes mellitus (IDDM) are studied and contrasted with similar characteristics in other, more conventionally sampled data sets. Some characteristics remain consistent with earlier observations including the high frequency of human leukocyte antigen (HLA) DR3,4 in affected individuals and the greater than expected percentage of HLA haplotype sharing among affected sib pairs. In other respects, however, differences are seen between this sample and others. “Control” haplotypes, i.e., those not transmitted to the first affected offspring, had a higher frequency of DR3 and DR4 than expected, and a rather high frequency of affected parents was observed. Differences between the first affected and later affected offspring reported in other samples were absent from these families. No effect of the sampling scheme and the resulting distribution of parental phenotypes could be shown to explain this difference.
Genes predisposing to IDDM in multiplex families
Authors: Field L. Leigh
Published: June 2005

Analysis of HLA haplotypes occurring in more than one, only one, or no diabetics in GAW5 multiplex insulin‐dependent diabetes mellitus (IDDM) families suggested: (1) DR3, DR4, DRw6, and DRw8 are positively associated, and DR2 is negatively associated, with IDDM; (2) DR4 haplotypes are more diabetogenic than DR3 haplotypes; some DR3 haplotypes lacking B8/B18 are more diabetogenic than those carrying B8/B18; DR3 haplotypes with DRβ TaqI bands [2,5,10/11] are more diabetogenic than those without; DR4 haplotypes that carry DQw3.2 are more diabetogenic than those that do not; some DR2 haplotypes are diabetogenic rather than protective. Analysis of DR3 and DR4 transmission from DR3/X and DR4wX (X ≠ 3,4) healthy parents suggested: (3) no distortion of transmission to healthy children and (4) mothers transmit DR4 (and perhaps DR3) less often than fathers to diabetic children. Analysis of INS, GM, and HLA haplotype sharing in affected sib pairs suggested: (5) random segregation of INS haplotypes and (6) a tendency to increased sharing of GM haplotypes in affected sib pairs who were HLA‐identical and DR3/4, compared with pairs who were not.
Association and sibpair analysis for the HLA, Gm, Km, and insulin polymorphisms in multiplex IDDM families
Authors: Fimmers R. , Neugebauer M. , Dennert J. , Wienker T. , Baur M. P.
Published: June 2005

A log‐linear model was used to analyze three‐way interactions between IDDM and pairs of genetic markers. To do this, a special sample dataset was selected by taking one affected and one unaffected child from each family. Some three‐way interactions were found for associations between insulin‐dependent diabetes mellitus (IDDM), HLA‐DR, and DQ restriction enzyme fragment length polymorphism (RFLP) patterns. No three‐way interaction was found for IDDM, HLA‐DR, and Gm or Km. An extended sibpair analysis was applied to the HLA‐B,DR loci and to the Gm, Km, and insulin gene polymorphisms. The well‐known result for IDDM and HLA was reproduced. For Gm, Km, and the insulin gene no cosegregation with IDDM could be found.
Genetic analysis of the affective disorders: Summary of GAW5
Authors: Rice John , Risch Neil
Published: June 2005

Participants in the Affective Disorders component of Genetic Analysis Workshop 5 had acces to five distributed data sets: (1) 187 families from the Collaborative Depression Study, (2) 202 families ascertained as part of the NIMH Family Studies on Affective Disorders, (3) a compilation of 46 pedigrees informative for X‐linked markers, (4) HLA typing on 116 kindreds from the Toronto‐Rochester Depression Study, and (5) 81 members of an Old Order Amish pedigree demonstrating linkage to markers on chromosome 11p. These databases are each summarized after a brief account is given of the genetics of the affective disorders and commonly used diagnoses.

The emphasis of the Workshop was methodologic, with contributions divided evenly between linkage and nonlinkage applications. Contributions are summarized under four substantive areas: regressive logistic models, segregation and other familial analyses, methodologic considerations in linkage analysis, and the relationship between HLA and affective disorders.
Linkage data on affective disorders in an epidemiologic context
Authors: Gershon Elliot S. , Goldin Lynn R.
Published: June 2005

Recent data on chromosomal linkage markers in affective disorders indicate that single locus inheritance is involved in these disorders. The presence of a single locus has not been detectable using segregation analysis on family study data from large populations, possibly because of both heterogeneity and birth cohort and sex differences in diagnostic frequencies.
The incomplete, multiple ascertainment model: Assumptions, applications, and alternative models
Authors: Stene Jon
Published: June 2005

Assumptions and applications of the widely used incomplete, multiple ascertainment model have been examined. The common use of a reduced version of the model by suppressing the information about independently ascertained probands leads to inaccurate and unstable estimates. The fact that many samples consist mainly of families ascertained through the first member who has the disorder may lead to seriously biased estimates of the segregation probability, as the model does not take this common ascertainment situation into account.
Linkage analysis under “random” and “genetic” reduced penetrance
Authors: Greenberg David A. , Hodge Susan E.
Published: June 2005

We examined whether the results of linkage analysis are affected by the reasons for so‐called “reduced penetrance”. We simulated linkage data with random reduced penetrance and contrasted that with data that were simulated under inheritance controlled by two loci interacting epistatically. For the two‐locus disease models, one of those loci was linked to the marker. All data, irrespective of how the data were simulated, were analyzed under the assumption of a single‐locus genetic model with random reduced penetrance. We found that there appears to be little bias in the results of linkage analysis whether the “reduced penetrance” was caused by random (usually interpreted as environmental) factors or by strictly genetic factors. We also illustrate that when the trait or disease is influenced by more than one locus, the inheritance of the trait at the linked locus is the important consideration, not the inheritance of the trait per se.
Analysis of the Toronto‐Rochester depression study follow‐up data confirms an HLA‐region gene contribution to susceptibility to affective disorder
Authors: Weitkamp L. R. , Stancer H. C.
Published: June 2005

Analysis of HLA haplotype distributions in relation to major affective disorder in affected sibling pairs and affected aunt or uncle and niece or nephew pairs confirmed that HLA‐region genes do contribute to susceptiblity to affective disorder. The data indicated that this effect may be greater in unipolar than in bipolar disorder, and more apparent in families with few affected members than in heavily loaded families. Nonrandom assortment of HLA haplotypes to affected and unaffected offspring in “low load” families occurred principally for the haplotype transmitted from the side of the family without affective disorder. We conclude that HLA‐region genes contribute to but are not the only factor in susceptibility to major depression.
Phenylthiocarbamide taste sensitivity revisited: Complete sorting test supports residual family resemblance
Authors: Reddy B. M. , Rao D. C. , MacCluer Jean W.
Published: June 2005

Phenylthiocarbamide (PTC) taste thresholds were determined in 100 nuclear families using the complete sorting test. Segregation analysis using the mixed model suggested that the variability in PTC thresholds is controlled by a major locus with incomplete dominance as well as by a multifactorial component with significant residual heritability. Such a model explained nearly 96% of the variance, leaving only 4% of the variance in thresholds arising from measurement error and other environmental factors.
Simulation of Huntington's disease onset
Authors: Markson Leona Enama , Chase Gary A. , Brookmeyer Ron , Rao D. C.
Published: June 2005

Previous investigators have noted that the type of sampling scheme used to study the natural history of Huntington's disease can affect the observed age of onset distribution. Simulated data are presented to demonstrate that bias is introduced when onset characteristics derived from prevalence samples (i.e., samples of affected individuals alive in the population) are used to evaluate cofactors of disease onset and to compute genetic risk estimates for persons “at risk” of developing the disease. This study demonstrates that prevalence sampling underestimates the proportion of Huntington's disease cases in the population with later onset ages. Using plausible values for onset time, duration, and life expectancy, simulation results suggest that the paternal transmission effect on Huntington's disease onset is overestimated when based on prevalence data.
The impact of altered fitness on the risk of illness in relatives
Authors: Kendler Kenneth S. , Maclean Charles J. , Rao D. C.
Published: June 2005

Altered fitness of affected individuals can substantially influence the pattern of risk of illness in relatives. This altered risk can result from both changes in the distribution of genotypes and changes in the genotype‐spcific proportion affected or GSPA. This report examines the impact of altered fitness on the GSPA in relatives of affected probands, under a simple genetic model. The model assumes that illness results from a generalized single major locus and that fitness is dependent only upon phenotype. It is shown that i) in progenitors of probands (e.g., parents and grandparents), GSPA can vary widely as a function of the fitness of affected individuals; ii) the change in GSPA is equal in parents and grandparents; and iii) in non‐progenitors (e.g., offspring, siblings, uncles/ aunts), GSPA is independent of fitness effects. The GSPA in parents and grandparents is a function both of the relative fitness of affected individuals (F) and the penetrance (Q) that can be approximated by the simple formula: GSPA = FQ/(FQ + 1 − Q). The successful application of model‐fitting methods for the detection of single gene variation to complex phenotypes that significantly alter fitness may, in certain circumstances, require the incorporation of “fitness effects” into the analytic model.
Phenotypic effects of apolipoprotein structural variation on lipid profiles: II. Apolipoprotein A‐IV and quantitative lipid measures in the healthy women study
Authors: Eichner J. E. , Kuller L. H. , Ferrell R. E. , Kamboh M. I. , Rao D. C.
Published: June 2005

Apolipoprotein A‐IV (APO A‐IV) is a major protein component of mesenteric lymph chylomicrons and very‐low‐density lipoproteins. It is found in plasma predominantly unassociated with major lipoprotein fractions and in high density lipoproteins. APO A‐IV exhibits structural heterogeneity owing to two codominant alleles, APO A‐IV*1 and APO A‐IV*2, that occur in Caucasian and black populations. In vitro experimental evidence indicates that APO A‐IV may be a cofactor for the lecithin:cholesterol acyltransferase enzyme, may be involved in reverse cholesterol transport, and may play an important role in the modulation of lipoprotein lipase activity. In this study we have investigated the effect of two APO A‐IV phenotypes, APO A‐IV 1–1 and APO A‐IV 2–1, on quantitative lipid measures in a group of 453 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. Of the nine lipid measures, triglycerides showed a marginally significant effect caused by phenotype. The APO A‐IV 2–1 heterozygotes had lower average triglycerides than the 1–1 homozygotes (P = .053).
Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin‐like growth factor II restriction fragment length polymorphisms
Authors: Ober Carole , Xiang Kun‐San , Thisted Ronald A. , Indovina Kelly Andrew , Wason Candace J. , Dooley Sharon , Rao D. C.
Published: June 2005

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. We have examined restriction fragment length polymorphisms (RFLPs) near “candidate diabetogenic genes” as one approach to identify molecular markers for GDM genes. Genotypes for insulin hypervariable region (HVR), insulin‐like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. Logistic regression analysis was used to explore the relationship between genotypes at these candidate gene loci and GDM, while adjusting for the effects of potential confounding variables. Among black subjects, the INSR allele 1 (P = 0.001) and interactions between INSR allele 1 with body mass index (BMI) (P = 0.002) and history of DM in subject's mother (P = 0.004) contributed significantly to GDM risk. Among Caucasian subjects, a similar relationship between the INSR allele 1 (P = 0.007) and INSR allele 1—BMI interactions (P = 0.011) on GDM risk were observed. In Caucasians, an additional significant risk factor was determined by an INSR allele 1—IGF2 allele 2 interaction (P = 0.018). No risk factors were identified in Hispanic subjects. These data continue to support the hypothesis that GDM is a heterogeneous disorder with respect to phenotypic and genotypic features. Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity per se but to interactions between obesity and INSR alleles. In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. Thus genes underlying susceptibility to GDM in some women may be similar to genes conferring risk to NIDDM, while in others novel genes may contribute to GDM risk.
Importance of hereditary disease at a Neuropsychiatric Institute in Mexico City
Authors: Alonso M. E. , Gomez L. , Otero E. , Figueroa H. H.
Published: June 2005

The objective of this study is to investigate the type, importance, and incidence of hereditary diseases in patients at the National Institute of Neurology and Neurosurgery in Mexico City. A review of 6,258 files indicated that hereditary diseases represent an important problem for the Institute: Of the diseases with the highest incidences, hereditary factors have an important role in seven (epilepsy, depression, facial palsy, schizophrenia, mental retardation, migraine, and Parkinson's disease). Diseases of known monogenic etiology represent 1.5% of all the cases.
Major gene polymorphism for human erythrocyte (RBC) thiol methyltransferase (TMT)
Authors: Price Richard Arlen , Keith Richard A. , Spielman Richard S. , Weinshilboum Richard M. , Vogler G. P. , Rao D. C.
Published: June 2005

Thiol S‐methylation is an important pathway in the metabolism of many sulfhydryl compounds including the antihypertensive drug captopril and the antirheumatic medication D‐penicillamine. Erythrocyte (RBC) thiol methyltransferase (TMT) activity was measured in blood samples from 237 individuals from 49 nuclear families. Earlier studies have demonstrated familial aggregation of RBC TMT activity, suggesting a role for genetic determinants. Our study indicates the specific mode of inheritance and gives relative contributions of a major locus and background genotype. We found evidence for a major locus, TMT. The aliele frequencies for low enzyme activity, TMTL, and high activity TMTH, estimated from a power transformed scale were 0.58 and 0.42, respectively. The high activity allele, TMTH, appears to have reduced expression in heterozygous individuals (d = 0.21) and to act in concert with a strong influence from polygenic genotype (H = 0.75) to produce a highly heritable phenotype. This major gene polymorphism may now be studied using biochemical and molecular genetic techniques.
Bivariate survival models for analysis of genetic and environmental effects in twins
Authors: Thomas Duncan C. , Langholz Bryan , Mack Wendy , Floderus Birgitta , Rao D. C. , Vogler G. P.
Published: June 2005

Classic methods in genetics for the analysis of binary attributes, based on an assumption of a “threshold” on a normally distributed latent variable called “liability,” estimate the strength of genetic and environmental effects from differences in correlations between relatives of differing genetic relatedness. Two problems that are not easily addressed by these methods are the need to take the age of onset into account (particularly in chronic diseases in which incidence rates vary considerably with age and the lengths of time at risk can vary between individuals) and the desirability of incorporating measured covariates (genetic or environmental). The standard methods of cohort analysis used in epidemiology allow for both of these features, but until recently have been restricted to independent individuals. Recent developments in survival analysis have extended the widely used “proportional hazards” model of Cox by the addition of latent variable, ε, reflecting the shared susceptibility of related subjects because of their shared genes or shared environment. We show how this approach can be combined with more traditional models of gene–environment interaction to allow the main effects of measured genetic markers and environmental variables to be estimated, as well as the residual variance of genetic and environment and their interactions. The approaches are applied to a cohort of female twin births in Sweden from 1886 to 1958, linked with the Swedish cancer registry from 1961 to 1982.
On the asymptotic behavior of the estimate of the recombination fraction under the null hypothesis of no linkage when the model is misspecified
Authors: Williamson John A. , Amos Christopher I.
Published: June 2005

We show that under the null hypothesis of no linkage the maximum likelihood estimator of the recombination fraction converges to 1/2 even when the trait‐related parameter values in the likelihood function are misspecified. Furthermore, we show that under the null hypothesis of no linkage, but with misspecified trait‐related parameter values, the negative of twice the natural logarithm of the likelihood ratio statistic still has a limiting chi‐square distribution with 1 degree of freedom.
Estimation of disease risk under bivariate models of multifactorial inheritance
Authors: Moldin Steven O. , Rice John P. , Van Eerdewegh Paul , Gottesman Irving I. , Erlenmeyer‐Kimling L. , Risch Neil J.
Published: June 2005

Adjunct consideration of both qualitative (affection status) and quantitative (correlated liability indicator) information to define a bivariate phenotype can increase considerably the accuracy and efficiency of disease risk estimation. A general approach for calculating morbid risks to offspring on the basis of parental affection status and an offspring quantitative trait is presented. We also describe two different bivariate models of multifactorial inheritance, as implemented in the computer programs POINTER and YPOINT, and make explicit their assumptions/constraints when estimating the within‐person and parent–offspring correlations necessary for calculation of morbid risks. We use psychometric family data on schizophrenia from the New York High‐Risk Project to estimate these correlations and illustrate our methods. Our results show that even when a trait is only moderately correlated with liability, incorporation of quantitative trait information can lead to resolution of a range of risk to offspring that is not possible through reliance on parental affection status alone. Bivariate models provide a useful methodology for incorporating quantitative indicators of liability in the investigation of genetically complex diseases.
A time‐dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases
Authors: Abel Laurent , Bonney George Ebow , Rao D. C.
Published: June 2005

The paper presents an extension of the regressive logistic models proposed by Bonney [Biometrics42:611–625, 1986], to address the problems of variable age‐of‐onset and time‐dependent covariates in analysis of familial diseases. This goal is achieved by using failure time data analysis methods, and partitioning the time of follow up inKmutually exclusive intervals. The conditional probability of being affected within thekth interval (k= 1…K) given not affected before represents the hazard function in this discrete formulation. A logistic model is used to specify a regression relationship between this hazard function and a set of explanatory variables including genotype, phenotypes of ancestors, and other covariates which can be time dependent. The probability that a given person either becomes affected within thekth interval (i.e., intervalkincludes age of onset of the person) or remains unaffected by the end of thekth interval (i.e., intervalkincludes age at examination of the person) are derived from the general results of failure time data analysis and used for the likelihood formulation. This proposed approach can be used in any genetic segregation and linkage analysis in which a penetrance function needs to be defined. Application of the method to familial leprosy data leads to results consistent with our previous analysis performed using the unified mixed model [Abel and Demenais,Am J Hum Genet42:256–266, 1988], i.e., the presence of a recessive major gene controlling susceptibility to leprosy. Furthermore, a simulation study shows the capability of the new model to detect major gene effects and to provide accurate parameter estimates in a situation of complete ascertainment.
On the asymmetry of biological frequency distributions
Authors: Schork Nicholas J. , Weder Alan B. , Schork M. Anthony , Rao D. C.
Published: June 2005

The long‐standing problem of determining whether the skewness in a sample frequency distribution is the manifestation of the intermixing of disparate groups characterizable by a normal mixture distribution or the manifestation of non‐mixture, skew‐producing determinants is discussed. Biometrical tools for modeling and quantifying the significance of the skewness in a trait of interest that invite interpretations other than those formed in mixtures or “subgroups” are elaborated. Statistical methods for testing whether a normal mixture distribution better characterizes a set of data than the proposed (or any other) skewed, single‐population‐oriented models are offered. The power of these tests is examined through Monte Carlo experimentation. A brief application in hypertension research demonstrates some of the problems and methods discussed in the paper.
Investigating the HLA component in rheumatoid arthritis: An additive (dominant) mode of inheritance is rejected, a recessive mode is preferred
Authors: Rigby Alan S. , Silman Alan J. , Voelm Lianne , Gregory Julie C. , Ollier William E. R. , Khan Muhammad A. , Nepom Gerald T. , Thomson Glenys , Vogler G. P.
Published: June 2005

We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA‐linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA‐DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P < 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well‐established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib‐pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA‐DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P < 0.001). The same results were obtained by an independent method which considered HLA‐DR transmission from affected parents to their affected children. The affected sib‐pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA‐linked locus on familiarity accounted for only a 1.61‐fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non‐HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.
Association of incident lung cancer with family history of female reproductive cancers: The Iowa women's health study
Authors: Sellers Thomas A. , Potter John D. , Folsom Aaron R. , Vogler G. P.
Published: June 2005

A number of studies have documented the familial aggregation of lung cancer; there is at least one report that female reproductive cancers are also increased in these families. To determine if the risk exists for all reproductive cancer sites, we conducted a nested case‐control study of lung cancer incidence in a cohort of 41,837 women ages 55–69 years. Women were recruited by mail and asked to provide information on education, occupation, smoking habits, physical activity, and family history of specific cancer sites among female relatives. Four year follow‐up for cancer incidence was conducted using a state‐wide tumor registry. Compared to random controls (n = 1900), cases (n = 152) were more likely to have reported at baseline a sister affected with cancer of the uterus [crude odds ratio (OR) = 3.4, 95% Cl = 1.7–7.0, P < 0.01], cervix (OR = 3.2, 95% Cl 1.2–8.6, P < 0.05), or cancer at any site (OR = 1.6, 95% Cl 1.1–2.4, P < 0.05). A family history of an affected mother with a female reproductive cancer was also more common among the cases, but not statistically significant. Cases were less educated, more likely to work in a technical/industrial setting, less physically active, more likely to smoke, and to smoke for a longer period of time than the controls (all P < 0.01). These differences reduced the magnitude of the family history risk indicators; only the combined category of reproductive cancer at all sites among sisters remained statistically significant. Additional family studies should be done to assess environmental factors in the relatives of the cases and controls to disentangle the influence of shared genes and shared environmental factors in these associations.
A temporary increase of down syndrome among births of young mothers in Norway: An effect of risk unrelated to maternal age?
Authors: Lie Rolv Terje , Heuch Ivar , Irgens Lorentz M.
Published: June 2005

The Medical Birth Registry of Norway carries out a population‐based surveillance of birth defects on a routine basis. An increased proportion of newborn with Down syndrome was seen among children of young mothers during 1985–1986. Three alternative explanations were considered: a first representing a maternal age specific effect, a second based on a general increase in a subgroup of cases caused by factors not related to maternal age, and a third based on the assumption that a particular birth cohort of young women was carrying a high risk. As 1987 and 1988 showed very low proportions in all age groups, the last explanation was considered less likely. Statistical modeling was used to explore which of the two remaining explanations of the temporary increase was the more likely. The observed changes were compatible with a change in the occurrence of a group of maternal age‐independent Down syndrome cases, from 4.59 per 10,000 in 1973–1984 and again in 1987–1988 to a temporary high of 7.68 per 10,000 in 1985–1986. However, the possibility of an age specific change only among young mothers could not be ruled out.
Linkage analysis of low‐density lipoprotein subclass phenotypes and the apolipoprotein B gene
Authors: LaBelle Michael , Austin Melissa A. , Rubin Edward , Krauss Ronald M. , Vogler G. P.
Published: June 2005

A common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low‐density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high‐density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three‐fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25–0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotyope B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3′ end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of −7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.
Estimating effects of probands' characteristics on familial risk: I. Adjustment for censoring and correlated ages at onset
Authors: Liang Kung‐Yee , Vogler G. P.
Published: June 2005

Family studies with age at onset of the disease as the endpoint face two important problems: censoring and correlation of age at onset among relatives. We present a multivariate survival model for ages at onset of relatives which incorporates the problems cited above. The interpretations of regression coefficients and association parameter in the context of family studies are emphasized. The present paper describes a statistical method for estimating these parameters. In a companion paper [Pulver and Liang,Genet Epidemiol8:339–350, 1991] this model is applied to a genetic epidemiologic study of schizophrenia.
Estimating effects of proband characteristics on familial risk: II. The association between age at onset and familial risk in the Maryland schizophrenia sample
Authors: Pulver Ann E. , Liang Kung‐Yee , Vogler G. P.
Published: June 2005

In this report we apply methods outlined in the companion paper [Liang,Genet Epidemiol8:329–338, 1991] to study the association between proband age at onset and familial risk among first‐degree relatives of 374 schizophrenic probands. The analyses take into consideration the potential problems of censoring and correlation of age at onset within families. All analyses were done by gender of the proband; age at onset was dichotomized. The results of the analyses of the male probands suggest that there is an increased risk of schizophrenia among the relatives of male probands who have an onset prior to age 17 when compared to relatives of male probands who have an onset later than 16. We did not find an association between age at onset and familial risk among the female probands, but this may be due to the smaller number of female probands and the lower power associated with the analyses.
Genetics of total serum IgE levels: A regressive model approach to segregation analysis
Authors: Meyers Deborah A. , Beaty Terri H. , Colyer Claudia R. , Marsh David G. , Vogler G. P. , Rao D. C.
Published: June 2005

The genetics of basal total serum IgE levels was investigated in 278 individuals from 42 randomly ascertained nuclear families. The data were analyzed using the regressive model approach to segregation analysis with age, sex, and a measure of skin test responsiveness as covariates in the Class D models. The best fitting model was that of recessive inheritance of high IgE levels with a gene frequency of 0.99 for the “high” allele. Only 3 families showed evidence for segregation of the rare “low” allele, and, if extended further, these families could be useful for molecular genetic linkage studies. These results suggest that there may be a rare allele for very low total serum IgE levels that can be detected even after a measurement of allergic responsiveness (skin test results) is considered as a covariate. Therefore, this major gene for IgE levels appears independent of any similar locus controlling atopy.
Effects of selective return on estimates of heritability for body mass index in the national heart, lung, and blood institute twin study
Authors: Selby Joseph V. , Reed Terry , Newman Beth , Fabsitz Richard R. , Carmelli Dorit , Vogler G. P. , Rao D. C.
Published: June 2005

In the National Heart, Lung, and Blood Institute Twin Study, body mass index (BMI) was studied at military induction and at three subsequent examinations spanning five decades in a cohort of white, male World War II veterans. At military induction (1940s) and again at the first clinical examination of this study (1969–1973), there was close agreement of three commonly used estimates of heritability (range 0.72 to 0.80), and no evidence of a difference in total variance of BMI between the zygosities. However, at the last two examinations (1980s), the total variance in dizygotic (DZ) twins was significantly greater than that of monozygotic (MZ) twins (P<0.01) and these same heritability estimates varied widely. The among‐pair estimate of heritability fell to unrealistic negative values, the within‐pair estimate rose to values of 1.0 or greater, and the intraclass correlation coefficient estimate was slightly lower than in the entire cohort at baseline. The cause of the unequal zygosity total variance appears to have been nonparticipation at later examinations of MZ twins with extreme values of BMI, with no evidence of a similar selection process influencing DZ twins. This selection process biased the three estimates of heritability, making it difficult to determine which estimate is the most appropriate. Despite these biases, it remains clear that genetic factors contribute substantially to BMI in this population.
Testing for association in SLE families
Authors: Seuchter Susanne A. , Knapp Michael , Hartung Klaus , Coldewey Rolf , Kalden Joachim R. , Lakomek Heinz J. , Peter Hans H. , Deicher Helmuth , Baur Max P. , Vogler G. P.
Published: June 2005

Systemic lupus erythematosus (SLE) is a complex disease which is partly determined by genetic factors which influence susceptibility to the disease phenotype. In this association study we try to define the high risk haplotypes which are responsible for this disease, together with other environmental factors. In many other association studies a set of SLE patients is compared to a set of controls. The basic assumption about the underlying population is that the disease and control sample should originate from the same genetic population, which is not always completely satisfied in many studies. Therefore, we analyse our family data by applying the Haplotype Frequency Difference (HFD) Method, which constructs its internal control group from those haplotypes not transmitted to the affected individual. Results partially conform with other studies, showing that the haplotypes B8 DR3 as well as B7 DR2 have a high positive association with SLE. When the DR locus was analyzed alone, we found besides the alleles DR2 and DR3 a negative association for DR1, DR5, and DR6.
Linkage studies of schizophrenia: A simulation study of statistical power
Authors: Chen Wei J. , Faraone Stephen V. , Tsuang Ming T. , Vogler G. P.
Published: June 2005

In planning for a linkage study, it is important to determine the number of pedigrees needed to show linkage. Our study overcomes some of the limitations of previous power studies by simulating multigeneration pedigrees to be compatible with the demographic and genetic epidemiological features of schizophrenia; these are variable age at onset, reduced fertility, and increased mortality after onset. We evaluate the power of these pedigrees by first simulating an ascertainment rule requiring at least three ill family members per pedigree and then simulating the trait and marker genotypes according to a single gene model known to fit epidemiological family study data. Our analysis allows for incomplete and age‐dependent penetrance, phenocopies, and interpedigree heterogeneity. We present the power to detect linkage at several lod score thresholds since the multiple tests and phenotypic models required for complex diseases may necessitate using a lod score significance level greater than three. The sample size needed to achieve sufficient power is feasible if 50% of the pedigrees are linked to the marker under test. It may not be feasible to detect linkage if only 25% of the pedigrees are linked, even if a very closely linked marker is used. Our results indicate that to be certain of adequate statistical power, linkage analyses of schizophrenia will require very large samples that do not have a marked degree of genetic heterogeneity. © 1992 Wiley‐Liss, Inc.
Detection of genetic heterogeneity for complex quantitative phenotypes
Authors: Schork Nicholas J. , Chakravarti Aravinda
Published: June 2005

Statistically characterizing factors responsible for quantitative phenotype expression (e.g., polygenes, major genes, shared household factors, etc.) through model selection strategies is a difficult task. A great deal of effort has been expended on refining mathematical and computational aspects of various segregation models used to characterize unique expressions of quantitative phenotypes in an effort to make these models easier to implement and evaluate for a given set of data. In this paper a slightly different angle is emphasized: namely, the explicit modeling of the potentially numerous heterogeneous genetic and environmental processes (i.e., segregation patterns, household aggregations, etiologic processes, etc.) that could contribute to the overall variation of a quantitative trait. As such, this paper describes tools for detecting quantitative trait heterogeneity that are meant to answer such questions as, ‘are there pedigress among a great many that show a pattern consistent with a possibly very specific single locus segregation pattern while the rest show compatibility with a polygenic or purely environmental pattern?’ Methods for determing the significance of such heterogeneity are also discussed, as are the results of numerous examples and simulation studies carried out in an effort to validate and further elaborate aspects of the proposed techniques. © 1992 Wiley‐Liss, Inc.
Variance components/major locus likelihood approximation for quantitative, polychotomous, and multivariate data
Authors: Hasstedt Sandra J.
Published: June 2005

Pearson [Philos Trans R Soc Lond [A] 200:1–66, 1903], Mendell and Elston [Biometrics 30:41–57, 1974], and Rice et al. [Biometrics 35:451–459, 1979] approximated the likelihood of the multifactorial model on a dichotomous phenotype by a procedure of successive univariate computation and conditioning. Hasstedt [Pap: Pedigree Analysis Package, Rev. 3. 1989] and Demenais [Am J Hum Genet 49:773–785, 1991] extended the algorithm to include a major locus. Here I extend the algorithm to polychotomous, quantitative, and multivariate phenotypes, add a major locus to the model, and describe and evaluate the accuracy of an approximation of the resulting variance components/major locus model. © 1993 Wiley‐Liss, Inc.
Inheritance of plasma apolipoprotein B levels in families of patients undergoing coronary arteriography at an early age
Authors: Coresh Josef , Beaty Terri H. , Kwiterovich Peter O.
Published: June 2005

An elevated plasma level of apolipoprotein B (apoB), the major protein of low density lipoproteins, is a risk factor for coronary artery disease. This study tested the hypothesis, suggested by previous studies, that the apoB level is strongly influenced by a major gene. The study population included 832 family members of 116 subjects who had undergone elective coronary arteriography at an early age. The apoB level was adjusted for age, gender, body mass index, alcohol consumption, and cigarette smoking (R2 = 20 %). ApoB levels revealed strong familial aggregation with correlations among spouses of 0.23, parent‐offspring of 0.16, and siblings of 0.21. Regressive models were used to examine inter‐individual variation in adjusted apoB levels. In the total sample, familial aggregation of the apoB level was consistent with two models: (1) a major gene model and (2) a polygenic model with a mixture of non‐transmitted “types.” Comparison of these two models in each family showed that 57 families supported the first model over the second. Segregation analysis in these 57 families conclusively favored a major gene model with codominant transmission. Genotypic means were 124, 164, and 208 mg/dl with relative frequencies of 45 %, 44 %, and 11 %. Linkage studies in these families can be used to clarify the molecular basis of apoB regulation. However, in the whole population the genetic control of apoB levels may be quite complex. © 1993 Wiley‐Liss, Inc.