bluuebunny/crossref_metadata_2025 huggingface dataset:
A general autosomal/X‐linked model
Authors: Hasstedt Sandra J. , Skolnick Mark , Rao D. C.
Published: June 2005

This paper describes a general genetic model which encompasses both autosomal and X‐linked inheritance as submodels. It allows one to test for X‐linked inheritance of a trait by comparing the likelihood of X‐linked inheritance to the likelihood of the general genetic model. The general model is formulated as two loci, the first representing the trait locus and the second representing the sex chromosomes. The test for X‐linked inheritance is a test of linkage between the two loci. Three data sets were analyzed using this approach. Each was also analyzed using a variant of a model introduced by Demenais and Elston [1981], which treats the transmission probabilities as estimable parameters. Similar conclusions were reached using either model.
Genetic covariation between neuroticism and the symptoms of anxiety and depression
Authors: Jardine R. , Martin N. G. , Henderson A. S. , Rao D. C.
Published: June 2005

A genetic analysis of the trait of neuroticism and symptoms of anxiety and depression in 3,810 pairs of adult MZ and DZ twins is reported. Differences between people in these measures can be explained simply by differences in their genes and in their individual environmental experiences. There is no evidence that environmental experiences that are shared by cotwins, such as common family environment or social influences, are important. There are differences between the sexes in gene action affecting neuroticism, and genetic effects become more pronounced with age in females. The lack of evidence for dominance variance affecting neuroticism contrasts well with the detection of considerable genetical nonadditivity for extraversion in the same sample and reinforces the view that these two traits are not only statistically, but also genetically, quite independent.

An analysis of the causes of covariation between anxiety, depression, and neuroticism shows that additive gene effects are more important causes of covariation than environmental factors. Genetic variation in symptoms of anxiety and depression is largely dependent on the same factors as effect the neuroticism trait. However, there is also evidence for genetic variation specific to depression.
Genetic analysis workshop II: Results of incorporating a linkage disequilibrium parameter
Authors: Goldgar David E. , Fain Pamela R.
Published: June 2005

The incorporation of a linkage disequilibrium parameter, Δ, into linkage analysis is illustrated for data from Genetic Analysis Workshop II. Points from a joint likelihood surface are calculated and displayed on a recombination fraction‐linkage disequilibrium grid using a simple modification of LIPED. The approach is shown to increase the power of linkage analysis and the power of tests for heterogeneity of linkage for the simulated examples.
Genetic analysis workshop II: Further consideration of segregation and linkage analyses in problem 3
Authors: Kramer P. L. , Altmann D. B. , Kidd K. K.
Published: June 2005

We analyzed disease‐marker associations in Problem 3 for the Genetic Analysis Workshop II, using PAP for segregation analysis and LIPED for linkage analysis. In this report we present aspects of our analyses that are not reported in the summary [MacCluer et al, 1984]. Certain features that we added to the running of LIPED to facilitate the analyses are discussed. Furthermore, we tested for Mendelian transmission in the hypothetical trait locus and we calculated modified relative risks for marker‐trait genotypes. Some of the problems involved in analyzing complex associations among loci are discussed.
The genetic susceptibility to insulin‐dependent diabetes mellitus: Combined segregation and linkage analysis
Authors: Green A. , Svejgaard A. , Platz P. , Ryder L. P. , Jakobsen B. K. , Morton N. E. , Maclean C. J. , Rao D. C.
Published: June 2005

We report a combined segregation and linkage analysis of a Danish sample of 216 insulin‐dependent diabetes mellitus (IDDM) nuclear families: of these 216, twenty multiplex families were haplotyped regarding HLA‐DR and ‐B markers. The analysis was conducted using the computer program COMBIN, which includes a modifier to absorb family resemblance that is additional to the effect of the major locus that is assumed linked to a marker locus, eg, within the HLA region. The initial analysis could clearly reject a dominant major locus but could not discriminate between other models with or without modifier. However, after adding supplementary information on population associations between HLA and IDDM together with the identity‐by‐descent (IBD) distribution to the analysis, a final model was identified. This invokes an additive major locus, linked to HLA with recombination not significantly different from 0, a disease gene frequency of 0.217, plus a dominant modifier. From this model it can be predicted that about 0.15% of the general population is at 100% risk of IDDM, about 5% is at intermediate risk (approximately 10%), while the remaining population has a risk of 0. The model predicts recurrence risks compatible with empirically estimated values. Particularly strong, positive haplotype associations were found for the DR3,B8, DR3,B18, and DR4,B15 haplotypes, but detailed analyses showed that neither these particular haplotypes nor the DR3 and DR4 haplotypes in general could entirely explain the HLA‐associated susceptibility. The DR2 haplotypes showed a strong negative association. The results are discusssed in the light of available data on the epidemiology of IDDM in order to provide a framework for further epidemiological studies.
Genetic analysis workshop III: Multipoint linkage analysis
Authors: Aston C. E. , Wilson S. R.
Published: June 2005

It is possible to obtain an invalid set of estimates for the pairwise recombination values from using two‐point linkage analysis. Development of a multipoint linkage analysis which estimates the joint recombination events in a multilocus system is outlined.
HLA antigens and acute rheumatic fever: Evidence for a recessive susceptibility gene linked to HLA
Authors: Hafez M. , Chakravarti A. , El‐Shennawy F. , El‐Morsi Z. , El‐Sallab S. H. , Al‐Tonbar Y. , Rao D. C.
Published: June 2005

From 60 probands with acute rheumatic fever (ARF), 19 multiplex families segregating for ARF were ascertained. The parents and rheumatic and normal sibs of the probands in these 19 families were also studied. HLA typing using the microlymphocytotoxic assay was then performed on the 60 unrelated probands, the multiplex families, and 234 unrelated controls using 23 antigens from the HLA‐A and ‐B loci. The controls lacked a past history of ARF and were from the same geographic locality. Calculations of relative risk demonstrate an increase of HLA‐B5 antigen in the 60 patients, but the result might not be significant from the point of view of multiple comparisons. Nevertheless, affected sib pairs from the multiplex families show 93% concordance for both or one HLA haplotype. A formal linkage analysis demonstrates that a recessive etiology is most likely (lod score of 3.3) with approximately 68% of cases being due to a gene closely linked to HLA and in linkage disequilibrium with HLA‐B5. The remaining 32% of cases are due to other familial factors such as polygenic inheritance or common environmental factors. The results confirm a strong genetic predisposition to ARF and its heterogeneous nature in families.
A multivariate analysis of familial associations of lipoprotein levels in the Lipid Research Clinics Collaborative Family Study: I. Familial correlation and regression analyses
Authors: Heuch Ivar , Namboodiri Kadambari K. , Green Philip P. , Kaplan Ellen B. , Laskarzewski Peter , Glueck Charles J. , Elston Robert C. , Rifkind Basil M. , Rao D. C.
Published: June 2005

In view of the complex, intraindividual relationships among different lipoprotein levels (LDL‐C, HDL‐C, and VLDL‐C), multivariate methods aimed at assessing joint familial associations and their possible determinants were performed in the white, random sample component of the Collaborative Lipid Research Clinics Family Study data (1,336 families with 5,097 subjects). After appropriate transformations and covariate adjustments of the data, several kinds of correlation and regression analyses were performed, taking into consideration variable family size and possible age and clinic differences. The association patterns across clinics and age strata were found to be homogeneous for the vast majority of comparisons. The results of multivariate analyses (especially the significant association of each lipoprotein among biological relatives), the persistence of parental levels as the best predictors for the same lipoprotein levels among the offspring, and the essentially unchanged partial correlation estimates as compared to ordinary correlations suggest strong influence of factors specific to each lipoprotein in the familial associations. But the highly significant intraindividual correlations and the nonnegligible cross‐correlations among relatives also suggest the additional presence of common underlying factors for the familial associations, especially between HDL‐C and VLDL‐C and to a lesser extent between LDL‐C and VLDL‐C. The issues stemming from these analyses and the directions for further analyses are discussed.
The inheritance of pyloric stenosis explained by a multifactorial threshold model with sex dimorphism for liability
Authors: Chakraborty Ranajit , Rao D. C.
Published: June 2005

The inheritance of pyloric stenosis is explained by a multifactorial threshold model with an underlying assumption that the liability for the disease is distributed in males and females showing a sex dimorphism. From the available data on familial occurrences of pyloric stenosis, it is shown, that an extra maternal effect is not required to explain the familial risk of pyloric stenosis, as opposed to the earlier literature. Explicit expressions for familial risks of a discontinuous trait exhibiting dimorphism of liability are presented, based on a model originally proposed by Rice et al [1981], which do not require the approximation of univariate normality of a conditional bivariate normal distribution.
Construction of human linkage maps: Likelihood calculations for multilocus linkage analysis
Authors: Lathrop G. M. , Lalouel J. M. , White R. L. , Rao D. C.
Published: June 2005

Methods are given for efficient calculation of the likelihood for multilocus linkage in families comprised of grandparents, parents, and children. Such families are being used in large‐scale cooperative efforts to build a detailed linkage map of the human genome. The methods are illustrated by an application to loci on chromosome 13.
Family history of cancer related to cholesterol level in young adults
Authors: Reed Terry , Wagener Diane K. , Donahue Richard P. , Kuller Lewis H. , Rao D. C.
Published: June 2005

Cancer family history was quantified in 229 subjects (122 female, 107 male) screened for total serum cholesterol as seventh graders in 1972–1973 and repeated nine years later as young adults. Division of the subjects on the basis of cholesterol quintile resulted in significantly lower cancer family history scores in participants with persistently low total serum cholesterol levels and a significant excess of cancer mortality in parents and grandparents of young adult males with highdensity lipoprotein (HDL) levels in the upper quintile. A trend toward increased cancer in families of young adults who were smokers was independent of the cholesterol levels. It is suggested that such a quantification of family history score will be more useful than simply designating the family history as positive or negative in future modeling schemes for predicting risk.
Testing for developmental changes in gene expression on resemblance for quantitative traits in kinships of twins: Application to height, weight, and blood pressure
Authors: Corey L. A. , Eaves L. J. , Mellen B. G. , Nance W. E. , Rao D. C.
Published: June 2005

Height, weight, and blood pressure measurements on identical and fraternal twins and their families were analyzed to assess the degree to which genetic effects may change with age. The blood pressure data were based on the total sample of 1,767 individuals, while height and weight were available on 1,640 individuals in 204 monozygotic twin kinships. The results of testing alternative hypotheses about developmental changes in gene expression indicate that different mechanisms may be operative for these traits. While there was no evidence that developmental effects are a significant source of the observed variation in systolic or diastolic blood pressure, there was strong evidence that genetically determined developmental changes are an important factor in the determination of body weight. Agerelated changes in weight appeared to be best explained by the cumulative developmental effects of a single set of genes, rather than by the expression of new genes at different stages of development.
Heterogeneity in multifactorial inheritance of plasma lipids and lipoproteins in ethnically diverse families in Jerusalem
Authors: Friedlander Y. , Kark J. D. , Stein Y. , Rao D. C.
Published: June 2005

Genetic and cultural determinants of total cholesterol (TC), triglyceride (TG), low‐ and high‐density lipoprotein cholesterol (LDL‐C, HDL‐C), and HDL‐C/TC were estimated utilizing a path model in a random sample of nearly 4,000 families examined in the Jerusalem Lipid Research Clinic. The analyses were done separately in each of the ethnic groups categorized according to the parents' country of birth (Europe, Asia, North Africa, and Israel/mixed origin) in order to identify the nature and sources of any heterogeneity among the the groups. Both genetic (h2) and cultural (c2) components of inheritance were significant for all lipid variables in each of the ethnic groups. Under the most parsimonious model, estimates of h2 in the ethnic groups were .40–.55, .40–.51, .45–.50, .41–.48, and .42–.78 for TC, LDL‐C, HDL‐C, HDL‐C/TC, and TG, respectively. The c2 ranged from 3% to 5% for TC and LDL‐C and from 4% to 10% for HDL‐C, HDL‐C/TC, and TG. The major parameters of the path model were generally homogeneous across the origin groups. The h2 appeared to be higher in the Asian and c2 was slightly greater in the European group. The stronger sibling environmental effect in the Asia group, the somewhat lower transmission of environment in the North African group, and the lower correlation between spouse environments in the North African group were the major sources of the origin heterogeneity. Within this population, genetic factors appear to be the major determinants of lipid variations, suggesting relative homogeneity of the distribution of environmental determinants of plasma lipids.
Cleft lip with or without cleft palate: Reanalysis of a three‐generation family study from England
Authors: Marazita Mary L. , Goldstein Alisa M. , Smalley Susan L. , Spence M. Anne , Rao D. C.
Published: June 2005

The study population consists of 424 three‐generation families originally ascertained through nonsyndromic cleft lip with or without cleft palate (CL ± P) surgical probands by Carter et al [J Med Genet 19:246–261, 1982] in London, England. Carter et al proposed that the multifactorial threshold model (MF/T) could explain the data. The goal of our study was to test that hypothesis, plus alternatives, rigorously.

Two approaches were used: 1) Carter et al had proposed that these data were consistent with the predictions of the MF/T as presented by Carter [Br Med Bull 25:52–57. 1969]. However, we tested those predictions using standard χ2 tests and found statistically significant departures from the predictions in these families. 2) Complex segregation analysis under the mixed model was performed. Again, the MF/T model could be rejected, as could a model of a major locus alone. The best‐fitting model included both major locus and multifactorial components. When the data were analyzed in two parts based on the proband's phenotype (CL vs CL + P) there was some evidence of heterogeneity in that there was a significant proportion of sporadic cases in the families of CL probands but not in the families of CL + P probands.

Our results provide no support for the MF/T model. The results from segregation analyses of CL ± P in these families were most consistent with autosomal major gene inheritance plus multifactorial contributions.
The recurrence risks for isolated cases with incompletely penetrant X‐linked conditions
Authors: Rogatko A. , Rao D. C.
Published: June 2005

The recurrence risks for an X‐linked disease with incomplete penetrance are evaluated for a sib given that an isolated proband (male or female) is affected. The derived formulae are applied to the X‐linked form of Alport and fragile X syndromes.
Analysis of the distribution of erythrocyte sodium lithium countertransport in a sample representative of the general population
Authors: Boerwinkle Eric , Turner Stephen T. , Weinshilboum Richard , Johnson Mark , Richelson Elliott , Sing Charles F. , Rao D. C.
Published: June 2005

Numerous studies of sodium‐lithium countertransport (Na‐Li CNT) have reported higher rates in essential hypertensives versus normotensive controls. We studied the distribution and the mode of inheritance of Na‐Li CNT using a sample of 238 unrelated individuals and a sample of 245 individuals in 50 pedigrees all sampled from the population at large. The distribution of Na‐Li CNT is continuous and bimodal. Our results indicate that there is a large genetic contribution to the distribution of Na‐Li CNT. The hypothesis that the effect that causes bimodality is transmitted from generation to generation is supported by the fit to these data of a restricted transmission model with τ2 = 0.749. We hypothesize that this deviation of τ2 from its Mendelian expectation may be attributable to heterogeneity in the etiology of the bimodality in the Na‐Li CNT distribution in the population at large.
Multipoint linkage analysis of spinocerebellar ataxia and markers on chromosome 6
Authors: Haines J. L. , Trofatter J. A. , Rao D. C.
Published: June 2005

Heterogeneity among the spinocerebellar ataxias (SCA) has been shown on clinical, biochemical, and genetic criteria. Among the autosomal dominant SCAs, several kindreds have shown loose linkage to the HLA loci on chromosome 6, while linkage in other kindreds has been rejected. The advent of multipoint linkage analysis allows the use of several marker loci simultaneously, thus increasing the amount of usable information. We have reanalyzed linkage data from a large kindred with SCA and provide evidence for a telomeric location of the SCA gene in this family. Knowledge of the relative gene location will ease the identification of the SCA gene by reducing the size of the chromosomal regions that must be examined.
Etiological heterogeneity in Hodgkin's disease: HLA linked and unlinked determinants of susceptibility independent of histological concordance
Authors: Chakravarti Aravinda , Halloran Susan L. , Bale Sherri J. , Tucker Margaret A. , Rao D. C.
Published: June 2005

Forty‐one multiplex families, from published sources and new data from the National Cancer Institute, segregating for Hodgkin's disease and HLA, have been studied. A reanalysis of these data strongly suggests a recessive mode of inheritance for susceptibility to Hodgkin's disease. The HLA haplotype sharing data between affected relatives demonstrate that approximately 60% of cases in multiplex families are due to an HLA‐linked susceptibility gene, the remaining 40% being due to other familial factors. The data clearly support the hypothesis of etiological heterogeneity for Hodgkin's disease, with both HLA‐linked and HLA‐unlinked factors being responsible. Finally, there is an increased concordance of histological types between affected relatives, but this concordance seems independent of HLA sharing.
Early onset periodontitis: A comparison and evaluation of two proposed modes of inheritance
Authors: Long Jeffrey C. , Nance Walter E. , Waring Patsy , Burmeister John A. , Ranney Richard R. , Rao D. C.
Published: June 2005

Two rare types of familial periodontitis, a localized form usually diagnosed in late adolescence, and a more generalized form with a latter mean age of diagnosis, have been analyzed with respect to genetic models currently favored in the dental literature. These include autosomal recessive and X‐linked dominant (partial penetrance) inheritance. Since there is variation in severity, extent, age of onset, altered sex ratio of affected individuals, and a low population prevalence, it is not surprising that genetic mechanisms heretofore have not been revealed.

We have compared the likelihoods of 33 kindreds ascertained through affected probands under the above genetic models. Our findings include (1) several families in which both forms of early onset periodontitis co‐occur, making it unlikely that the clinical varieties of the disease have unrelated genetic causes; (2) the autosomal recessive model is far more likely than the X‐linked dominant model. The superiority of the recessive hypothesis arises from the fact that there are only a few instances of affected individuals having affected parents and because the skewed sex ratio is shown to be incompatible with X‐linked inheritance. These conclusions are largely insensitive to the assumptions of the analysis. We conclude that the X‐linked dominant hypothesis is inadequate, and while the autosomal recessive model is by no means proven, it is clearly favored.
A family study of panic disorder
Authors: Hopper John L. , Judd Fiona K. , Derrick Peter L. , Burrows Graham D. , Rao D. C.
Published: June 2005

Panic disorder, as defined by the DSM III diagnostic criteria, was diagnosed in 117 probands for whom age of onset ranged from 10 to 59 years, with a mean of 26.6 years. Diagnosis of parents and siblings was based on interviews with the probands, and only those with “definite” panic disorder by the FISC criteria were considered to be affected. The pattern of concordances for panic across different groups of relatives was estimated concurrently by a log‐linear model for binary pedigree data, assuming different values for the cumulative risk. When an adjustment for age was made, based on the age of onset of probands, there was no significant difference between parent‐offspring concordance and sibling concordance. There was a negative, but not significant, concordance between spouse pairs. Assuming the lifetime cumulative risk was 1.9% for males and 4.7% for females, values considered appropriate for this population, our model predicted that the presence of an affected parent or sibling incurs an approximately five times increase in the risk of developing panic disorder. Our model assumes in effect that this risk is multiplied for each further affected relative. Although the common concordance across relationship groups is consistent with a genetic hypothesis, it can also be explained by common family environmental factors. There is a need for further pedigree studies, using twins and relatives, for example, and reliable information on the cumulative risk.
Genetic epidemiology of cleft lip with or without cleft palate in the population of Hawaii
Authors: Chung C. S. , Mi M. P. , Beechert A. M. , Borecki I. B.
Published: June 2005

Orientals consisting of Japanese, Chinese, Koreans, and Filipinos are clearly at higher risk for cleft lip with or without cleft palate [CL(P)] than whites, Puerto Ricans, and Hawaiians/part‐Hawaiians in Hawaii. Using the model of diallele cross, CL(P) incidences in incrosses and outcrosses involving 564,002 live births distributed among 669 mating types were analyzed to study the extent of major gene involvement in the difference in the two groups and to investigate maternal effect in the etiology of CL(P). CL(P) cases excluding syndrome cases were classified into two types: all CL(P) cases and CL(P) cases without additional malformations. For either type there was no evidence to suggest that simple major gene plays a dominant role in accounting for racial differences as measured by deviations from additivity in the hybrids. For CL(P) cases without additional defects, a negative “maternal effect” was detected in Filipinos such that higher risk for this racial group depends on when the father is Filipino. Implications of the findings are discussed.
Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer
Authors: Goldstein AM , Haile RWC , Hodge SE , Paganini‐Hill Ann , Spence MA , Rao D. C.
Published: June 2005

We investigated the segregation pattern of breast cancer in families with bilateral breast cancer, classifying families with respect to menopausal status (premenopausal versus postmenopausal) and the interval between diagnosis of the two primary tumors in the probands. Probands were “synchronous” if both primaries were diagnosed within 1 year; “asynchronous” if the interval was at least 2 years. Results for four complex segregation analyses are here presented; the findings support heterogeneity in the transmission of breast cancer. In the asynchronous premenopausal‐cases‐only analysis, a dominant Mendelian gene can explain the breast cancer pattern. A recessive gene is sufficient to describe the breast cancer distribution in the synchronous premenopausal‐cases‐only analysis. The synchronous all‐cases and the asynchronous all‐cases analyses add postmenopausal cases of breast cancer to the premenopausal ones, considering any case to be affected. In the asynchronous all‐cases analysis, neither the single‐locus model nor the mixed model (that is, a major locus plus other factors, genetic and/or cultural) without generation differences in heritability can be rejected by the unrestricted mixed model with generation differences in heritability. For the synchronous all‐cases analysis, a mixed model with generation differences in heritability is necessary to explain the breast cancer transmission. Potential sources of error and possible interpretations are discussed.
Genetic analysis of IDDM: The GAW5 multiplex family dataset
Authors: Baur M. P. , Fimmers R. , Fritsche C. , Hümmelink M. , Neugebauer M. , Acton R. T. , Hodge T. , Barbosa J. , Bertrams J. , Fehsel K. , Kolb H. , Rothe H. , Boehm B. , Cambon‐Thomsen A. , Avoustin P. , Coppin H. , Darnaud J. , Massabie P. , Ohayon E. , de Preval C. , Tauber J. P. , Thomsen M. , Colle E. , MacDonald M. J. , Nevin D. , Gottschall J. L. , Nepom G. T. , Robinson D. M. , Holbeck S. , Palmer J. P. , Nerup J. , Rotter J. I. , Vadheim C. , Rittner C. , Schneider P. , Sheehy M. J. , Cox N. J. , Baker L. , Spielman R. S.
Published: June 2005

In a collaborative effort by 12 centers from Europe and North America, data were assembled from 94 multiplex families with insulin‐dependent diabetes mellitus (IDDM) for analysis of genetic and other factors of possible etiological importance. The dataset contains information on the following genetic markers: HLA‐DRß and ‐DQß restriction fragment length polymorphisms (RFLPs), three RFLPs detected with two probes that map 5′ to the insulin gene, the serologically defined HLA loci, and the immunoglobulin allotypes. Data also were included for auto‐antibodies to insulin and pancreatic islet cells as possible indicators of pathogenesis and for antibodies to certain viruses that have been implicated as “triggering” agents in IDDM. Medical histroy of family members was obtained by means of a uniform questionnaire. Identical copies of the dataset were distributed to anyone wishing to participate in the analysis for the IDDM component of GAW5. The multiplex IDDM family dataset is now available on request for further analysis.
Segregation analysis of two genetic markers in IDDM families under two‐locus models
Authors: Dizier Marie‐Hélène , Clerget‐Darpoux Françoise , Hochez Joëlle
Published: June 2005

The purpose of our study was to examine evidence for the role of a second genetic factor in the susceptibility to IDDM, in addition to that located in the HLA region. To do this, we have studied the joint segregation of HLA and another marker conditional on disease status using the IDDM families of GAW5, under a two‐locus model, one locus in the HLA region, the other close to the other marker. This marker has been, successively, Gm and the DNA polymorphism of the insulin gene 5′ region. The study has been carried out using a segregation analysis method developed to make use of information on the segregation of two markers and the disease in nuclear families. The GAW5 data do not provide evidence for the role of a genetic factor in the Gm or insulin region in the etiology of IDDM.
Statistical properties of the haplotype relative risk
Authors: Ott Jurg
Published: June 2005

In the haplotype relative risk (HRR) statistic (Rubinstein et al.: Human Immunol 3:384 [abstract], 1981), a disease sample is constructed along with its own internal control by comparing those marker alleles passed from the parents to an affected child with the other parental marker alleles not transmitted. Based on the conditional parental genotype distribution given that they have an affected child, statistical properties of the HRR statistic are derived. It is shown that the HRR is different from 1 only when allelic association is present and the recombination fraction is different from 1/2. Transmitted and nontransmitted marker alleles are shown to be statistically independent only in the absence of either allelic association or recombination.
Genetics of IDDM: Evidence for complex inheritance with HLA
Authors: Risch Neil
Published: June 2005

Analysis of the Fifth Genetic Analysis Workshop (GAW5) insulin‐dependent diabetes mellitus (IDDM) data leads to the following conclusions: (1) With a maximum‐likelihood affected sib pair method, there is strong evidence for linkage with HLA and no evidence for linkage with INS, Gm, or Km. (2) Susceptibility as defined by HLA genotypes is very complex. Each DR allele has a unique susceptibility, and DR3 and DR4 haplotype associations for DR 3/4 genotypes are different from those for 3/X and 4/X. (3) Risk is substantially higher in sibships with an affected father compared to those with an affected mother. This excess cannot be attributed to transmission distortion at HLA.
HLA DQβ3.2 identifies subtypes of DR4 + haplotypes permissive for IDDM
Authors: Robinson David M. , Holbeck Susan , Palmer Jerry , Nepom Gerald T.
Published: June 2005

The HLA class II‐related susceptibility to type I insulin‐dependent diabetes mellitus (IDDM) is examined in 94 multiplex families sorted by the presence or absence of a DR4+ haplotype in at least one diabetic family member. The families with DR4+ haplotypes are then sorted by the presence or absence of a DR4‐linked DQβ3.2 allele. Further analysis assumes each multiplex family to represent a single diabetic genetic event and identifies the HLA class II haplotype(s) present in all affected members. The DQβ3.2 allele is present in over 95% of the multiplex families where DR4+ haplotypes segregate with IDDM, implying a major permissive role in determining susceptibility to IDDM.
HLA and insulin gene associations with IDDM
Authors: Thomson G. , Robinson W. P. , Kuhner M. K. , Joe S. , Klitz W.
Published: June 2005

The HLA DR genotype frequencies in insulin‐dependent diabetes mellitus (IDDM) patients and the frequencies of DR alleles transmitted from affected parent to affected child both indicate that the DR3‐associated predisposition is more “recessive” and the DR4‐associated predisposition more “dominant” in inheritance after allowing for the DR3/DR4 synergistic effect. B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing Haterogeneity is detected for both the DR3 and DR4 predisposing haplotypes based on DR genotypic class. With appropriate use of the family structure of the data a control population of “unaffected” alleles can be defined. Application of this method confirms the predisposing effect associated with the class 1 allele of the polymorphic region 5′ to the insulin gene.
Age of onset, age at examination, and other covariates in the analysis of family data
Authors: Elston R. C. , George V. T.
Published: June 2005

Information on age of onset can easily be incorporated into regressive logistic models by assuming that age of onset follows a logistic distribution. This is analogous to previously proposed models based on the normal distribution. The two distributions, and hence the two types of models, are very similar. In each case the generalized modulus power transformation can be used as a basis for more flexibly modeling the age of onset distribution.
Familial correlates of risk: Application to the gershon and goldin NIMH pedigree data
Authors: Gilligan Sheila B. , Rice John P.
Published: June 2005

Survival analysis of familial covariates of risk for affective illness demonstrated a significant effect on the proband's diagnosis when affection status included bipolar illness, but not major depressive disorder. A cohort effect was indicated only when broad spectra (including bipolar II and major depressive disorder) of illness were defined. Multifactorial analyses of familial correlations for affective illness evidenced neither sex‐specific correlations nor prevalences. We suggest the examination of risk variables prior to undertaking familial analysis.
A more powerful robust sib‐pair test of linkage for quantitative traits
Authors: Amos C. I. , Elston R. C. , Wilson A. F. , Bailey‐Wilson J. E. , Rao D. C.
Published: June 2005

A more powerful robust test for linkage is developed from the methodology of Haseman and Elston [Behav Genet 2(1):3–19, 1972]. This new robust test uses weighted least‐squares (WLS) methods to detect linkage between a quantitative trait and a polymorphic marker. For comparison, the characteristics of a test for linkage that uses known trait genotypes for the parents are also studied. Sample sizes needed to detect linkage, calculated using asymptotic results, are compared for 1) the usual Haseman‐Elston method, 2) the WLS method, and 3) the method that uses parental trait genotype data. The WLS method needs at most twice the number of sib pairs as does the method that used information on the trait genotypes of the parents. The small sample properties of the Haseman‐Elston (H‐E) and WLS tests are investigated by simulation. The power calculations for the H‐E method are found to be accurate. The power of the WLS method is overestimated when fewer than 300 sib pairs are studied, but the WLS method is nonetheless more powerful than the usual H‐E method. In samples of fewer than 300 sib pairs, the WLS test tends to be anticonservative. Treating all sib pairs from sibships of size 3 or 5 as independent does not increase the significance of the tests.
Genetic studies on an Alzheimer Clinic population
Authors: Sadovnick A. D. , Irwin M. E. , Baird P. A. , Beattie B. L. , Conneally P. M.
Published: June 2005

All patients attending the Clinic for Alzheimer Disease and Related Disorders have detailed family histories taken by a geneticist. To date, genetic histories are available for 446 consecutive, unrelated individuals. Of these, 151 (33.9%) are diagnosed as having “probable” (N = 141) or “autopsy‐confirmed” (N = 10) Alzheimer disease according to recognized criteria. This data base represents a relatively unselected population with respect to more than one person in the family having dementia.

Seventy‐one of these 151 index cases (47.0%) have a positive family history of dementia, of which 8 (5.3%) may represent the familial (autosomal dominant) form of Alzheimer disease (FAD).

Age‐corrected empiric recurrence risks for Alzheimer disease/dementia were calculated for first‐degree relatives of these 151 index cases using the Kaplan‐Meier lifetable method.
Availability of schizophrenic patients and their families for genetic linkage studies: Findings from the Maryland epidemiology sample
Authors: Pulver Ann E. , Bale Sherri J. , Rao D. C. , Vogler G. P.
Published: June 2005

It has been suggested that collections of affected sib pairs, or their nuclear families, may be an efficient method for screening for genetic linkages in schizophrenia. We present the data collected in five years from 15 hospitals in the state of Maryland in an effort to determine if such a collection scheme will be feasible. Probands in our sample were eligible for inclusion in the sample if they were white, were age 16 years or older, and carried a research diagnosis of schizophrenia. Family data are reported for 258 probands. Using the most stringent category of affected (RDC schizophrenia) revealed ten families with two or more affected sibs. The broadest category of affected (any psychotic disorder or psychiatric hospitalization) identified only 36 families with two or more affected sibs. We conclude that, if schizophrenia is a heterogeneous disorder with decreased penetrance, an effort to collect multiplex nuclear families is unlikely to provide enough data to identify genetic linkage. Alternatively, an effort to seek out and collect larger multiplex, multigenerational families rather than a collection of affected sib pairs may be more efficacious.
Phenotypic effects of apolipoprotein structural variation on lipid profiles. IV. Apolipoprotein polymorphisms in a small group of black women from the Healthy Women Study
Authors: Eichner J. E. , Kuller L. H. , Ferrell R. E. , Kamboh M. I. , Vogler G. P. , Rao D. C.
Published: June 2005

Structural variation in apolipoprotein E has been shown to influence lipid and lipoprotein concentrations. The purpose of the present study was to investigate several apolipoproteins in a group of Black women from the Healthy Women Study (HWS). HWS is a community‐based prospective study of 541 premenopausal women who are being followed through the menopause to determine the influence of biological, genetic, and psychosocial phenomenon on cardiovascular risk factors. Of the 541 subjects, 48 are Black. Serum from most of these 48 Black women was used to type seven apolipoproteins (APO A‐I, APO A‐II, APO A‐IV, APO C‐II, APO D, APO E, and APO H). Five of these apolipoproteins are polymorphic in Blacks (APO A‐IV, APO C‐II, APO D, APO E and APO H). Only two and three individuals, respectively, were heterozygous at the APO D and APO C‐II loci. APO A‐IV, E, and H exhibited more variation, however, only APO E phenotypes could be used for statistical analyses. Three common phenotypes, APO E 3–2, APO E 3–3, and APO E 4–3, were used in analysis of variance on four quantitative lipid variables. Despite small numbers, the effect of APO E phenotype was apparent. The APO E 3–2 phenotype showed reduced average levels of total cholesterol, apolipoprotein B (APO B) and low‐density lipoprotein cholesterol (LDLC), and the APO E 4–3 phenotype showed increased levels (P ≥ .0497). The APO E 3–3 homozygote was intermediate on all three. Because of small numbers in the cells of APO A‐IV and APO H phenotypes, these were not analyzed with respect to quantitative lipids.
On the role of vitamin D binding globulin in glucose homeostasis: Results from the San Luis Valley diabetes study
Authors: Iyengar Sudha , Hamman Richard F. , Marshall Julie A. , Majumder Partha P. , Ferrell Robert E. , Rao D. C. , Vogler G. P.
Published: June 2005

Several studies have reported association between noninsulin‐dependent diabetes mellitus and GC, the vitamin D binding protein of human plasma, with the GC 1 allele in significant excess among diabetics. Additionally, there is a considerable body of animal data suggesting that vitamin D has a significant impact on insulin secretion. Examination of the insulin levels in Dogrib Indians showed that the lowest levels of fasting insulin were associated with the GC 1F‐1F genotype. The present study examined levels of glucose, C‐peptide, and insulin at fasting and 1 hr and 2 hr following a 75 g oral glucose challenge, in a population of Hispanic‐Americans and Anglos in the San Luis Valley of southern Colorado. The sample comprised a total of 468 individuals with normal glucose tolerance. Of these, 289 were Anglos and 179 were Hispanic‐Americans. An analysis of covariance was performed to determine the effect of the GC genotypes on mean levels of the primary variables—glucose, C‐peptide, and insulin—and a secondary variable—insulinogenic index adjusting for the covariates age, body mass index (BMI), gender, and ethnicity. The analyses revealed that there is a significant difference in mean levels of glucose at fasting (F value = 2.46; P = 0.033) among the GC genotypes in the sample. Additionally, the differences in mean levels of 1 hr postprandial glucose among the GC genotypes although not significant at a 5% level, were significant at the 10% level. No other significant phenotypic effects were observed. These analyses, are not in concordance the results of an earlier study, where lower fasting insulin was associated with the GC 1F‐1F genotype.
Segregation analysis of quantitative traits in nuclear families: Comparison of three program packages
Authors: Konigsberg Lyle W. , Kammerer Candace M. , MacCluer Jean W. , Rao D. C. , Vogler G. P.
Published: June 2005

Segregation analysis frequently is used to test for the presence of major gene effects and to estimate the various genetic and environmental components contributing to diseases. Recent advances in both theoretical models and computational algorithms have provided a number of new programs for performing segregation analyses. We compared two newer programs: REGC (part of the package “SAGE”) and FISHER/MENDEL with an older established program (PAP) to determine relative accuracy in recovering parameter values and asymptotic standard errors, ability to discriminate between alternative transmission models, and execution speeds. Each program was applied to a set of computer simulations of a quantitative trait generated under a variety of genetic models. The results of these comparisons indicated that all the programs provided very similar parameter estimates, but that they differed in their abilities to identify the correct mode of transmission. In our simulations, PAP more often led to the selection of the correct transmission model, whereas REGC frequently indicated the presence of a major gene in simulations of purely polygenic transmission. Relative speeds for the programs differed, and their rank ordering varied with the complexity of the model being fitted. Although REGC was the fastest program for fitting a major gene or mixed model, it was by far the slowest program for estimating parameters in a sporadic or polygenic model.
Using factor scores to detect G × E Interactive Origin of “pure” genetic or environmental factors obtained in genetic covariance structure analysis
Authors: Molenaar P. C. M. , Boomsma D. I. , Neeleman D. , Dolan C. V. , Rao D. C. , Vogler G. P.
Published: June 2005

Moment expressions for individual factor scores can serve as simple tests for the presence of a particular class of interaction factors that are disguised as pure genetic and/or environmental factors. That is, individual genetic and environmental factor scores may be used to construct fourth‐order moments of these factors in order to test whether a common genetic or environmental factor in the multivariate genetic factor model is in fact of the interactive origin concerned. Expected fourth‐order moments are derived for cases with and without interaction. Application of fourth‐order moments of factor scores to detect interactive origin of common factors is illustrated with simulated twin data.
Biochemical intermediates in α1‐antitrypsin deficiency: Residual family resemblance for total α1‐antitrypsin, oxidized α1‐antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus
Authors: Silverman E. K. , Province M. A. , Campbell E. J. , Pierce J. A. , Rao D. C. , Martin N. G.
Published: June 2005

α1‐antitrypsin (α1AT) deficiency is variably associated with the development of pulmonary emphysema. To gain insight into the process which begins the Z point mutation at the Protease Inhibitor (Pi) locus and results in the variable development of emphysema, three quantitative phenotypes, including total α1AT, oxidized α1AT, and total immunoglobulin E (IgE), were measured in sera from α1‐antitrypsin‐deficient individuals and their families.

The mean and variance effects of the Pi locus on these biochemical phenotypes were removed, and path analysis of the residual phenotypes was performed by using a TAU model to investigate whether there was any additional multifactorial transmission. Significant transmission was demonstrated for total serum IgE and serum‐oxidized α1AT, which could be due to major genes other than the Pi locus, polygenes, or familial environment.

Segregation analysis of the residual phenotypes was performed to determine whether additional major gene effects, other than the Pi effect, influence these quantitative phenotypes. Convincing evidence for an additional major gene was not found for oxidized α1AT, total α1AT, or IgE.
Genetic epidemiology of differences in low‐density lipoprotein (LDL) cholesterol concentration: Possible involvement of variation at the apolipoprotein B gene locus in LDL kinetics
Authors: Houlston R. S. , Turner P. R. , Lewis B. , Humphries S. E. , Rao D. C.
Published: June 2005

Circulating levels of low‐density lipoprotein (LDL) vary considerably within and between populations, paralleled by differing coronary heart disease (CHD) mortality rates. We have previously shown that variation in the apolipoprotein (apo) B gene as associated with certain restriction fragment length polymorphisms (RFLPs) influences the metabolism of LDL in the U.K. population. To investigate a possible genetic contribution to variation in LDL levels in differing populations we have extended this original study. RFLPs of the apo B gene were determined in samples of individuals from the United Kingdom, Finland, Italy, Spain, and Africa. Significant associations of LDL fractional catabolic rate with the apo B EcoRI and XbaI RFLP genotypes were detected only in the two North European populations. In the African population sample, the XbaI RFLP displayed a significant association with LDL apo B synthesis. The data suggest that variation in the apo B gene influences the metabolism of LDL and that it is different in individuals of different ethnic background.
Assessing the effect of multiple linkage tests in complex diseases
Authors: Clerget‐Darpoux Françoise , Babron Marie‐Claude , Bonaïti‐Pellié Catherine , Rao D. C.
Published: June 2005

The significance of a lod score value of 3 is very difficult to assess in linkage studies between a genetic marker and a complex disease. One reason is that multiple tests may have been performed, voluntarily or otherwise. For the same disease, linkage may be tested by different laboratories with several markers under various genetic models and diagnostic schemes for the disease. In such a case, we show that the probability of getting a lod score value of 3 under independent transmission of the disease and the marker may be not negligible.