bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate segregation analysis using the mixed model
Authors: Blangero John , Konigsberg Lyle W. , Vogler G. P.
Published: June 2005

Most major genes involved in the etiology of complex diseases are likely to have pleiotropic effects on a number of intervening quantitative traits. Methods of segregation analysis that incorporate the additional information from such multiple traits will exhibit greater power for detecting the effects of major genes and allow explicit tests of major locus pleiotropy hypotheses. In this study, we present a new method for multivariate segregation analysis that utilizes a multivariate generalization of Hasstedt's [1982] technique for calculating approximate mixed model likelihoods on pedigrees. The method is based on a simplification of the multivariate conditional likelihood via a transformation that simultaneously orthogonalizes the residual additive genetic and environmental covariance matrices. This transformation allows the multivariate conditional likelihood to be factored into the product of independent univariate conditional likelihoods. Resulting computations are relatively fast, making it feasible to analyze multiple traits in extended pedigrees. We demonstrate our method with a bivariate analysis of high‐density lipoprotein cholesterol (HDL‐C) and apolipoprotein AI (apo AI) serum levels in 585 pedigreed baboons.
Affected kin‐pair IBD methods: Genetic models
Authors: Motro Uzi , Thomson Glenys , Vogler G. P.
Published: June 2005

Cases of interest using affected sib‐pair methods to distinguish between recessive and additive (dominant) modes of inheritance of a disease‐predisposing gene involve goodness‐of‐fit tests with a small expected number in the “share‐zero parental haplotypes” category, as well as an unknown parameter, the frequency of the disease‐predisposing allele. Our simulations demonstrate that the real significance level of the chi‐square test using the three‐haplotype‐sharing IBD values (share 2, 1, and 0 parental haplotypes) is close to the assumed (.05) level in these cases, so that the haplotype‐sharing classes do not have to be lumped, which would leave no degrees of freedom for a statistical test. The validity of the chi‐square approximation in cases of small expected freqencies has previously been described, but the situations that have been considered do not cover the very small values in the share‐zero category that are often expected in the affected sib‐pair analysis, nor do they involve estimation of an unknown parameter. Although including IBD values from affected kin pairs other than sibs can be a very powerful tool in demonstrating linkage of a marker and disease, these pairs do not add power, in fact they reduce the power, of the chi‐square tests of goodness‐of‐fit of modes of inheritance.
Measuring familial aggregation by using odds‐ratio regression models
Authors: Liang Kung‐Yee , Beaty Terri H. , Vogler G. P.
Published: June 2005

Detection of familial aggregation of a disease is important for studying possible genetic and environmental factors contributing to disease etiology. Accurate quantification of familial aggregation can provide guidance for subsequent, more sophisticated genetic studies. This article presents a statistical model and method for detecting both inter‐ and intra‐class aggregation of a binary trait with family data. The method used here is based on the logistic regression model which incorporates effects of individual covariates while measuring familial aggregation of risk as the odds ratios among classes of relatives. An estimation equation approach is presented where the joint distribution of binary traits among family members need not be fully specified. Data from a genetic epidemiologic study on liver cancer in Shanghai are analyzed for illustration, and reveal strong aggregation of risk even after adjusting for covariates. Effects of non‐random sampling and ascertainment bias are also discussed.
Apolipoprotein B‐gene DNA polymorphisms (Xbal and EcoRI), serum lipids, and apolipoproteins in healthy Chinese
Authors: Saha N. , Tay J. S. H. , Humphries S. E. , Vogler G. P.
Published: June 2005

The frequency of restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene, detected by XbaI and EcoRI, and their influence on serum lipids and apolipoproteins were studied in healthy Chinese of both sexes in Singapore. A total of 221 subjects (150 males, 71 females) were investigated for the XbaI and 159 subjects for the EcoRI polymorphisms, while serum lipids and apolipoprotein levels were available for 196 subjects. The frequency of the X2 allele was found to be significantly lower in the Chinese than that reported in Caucasians from the United Kingdom (0.09 vs. 0.51, P < 0.001). The haplotype frequencies were also significantly different between the Chinese and Caucasians with a higher frequency of XlRl in the former compared to the latter (0.85 vs. 0.34, P <0.0001). The distribution of RFLP genotypes at both of the restriction sites was at Hardy‐Weinberg equilibrium in all groups. The influence of the apo B RFLPs on serum lipids and apolipoprotein levels (apo AI, AII, and B) was studied by both residual and multiple regression analyses considering age, sex, body mass index (BMI), and genotypes as independent variables in all possible combinations. No association was observed between the apo B genotypes and serum lipids or apolipoprotein levels except for high density lipoprotein cholesterol (HDLC), apo AI and AII, with the X2 being associated with significantly lower levels of HDLC as well as apo AI and AII, the effect being stronger in males. These data raise the possibility that the mechanism of reported association between apo B polymorphism and coronary artery disease may be through effects on HDLC. © 1992 Wiley‐Liss, Inc.
Genetic and environmental effects on blood pressure in a Norwegian sample
Authors: Tambs Kristian , Moum Torbjørn , Holmen Jostein , Eaves Lindon J. , Neale Michael C. , Lund‐Larsen Per G. , Naess Siri , Vogler G. P.
Published: June 2005

Systolic (SBP) and diastolic (DBP) blood pressures were measured in a health screening of the adult population in Nord‐Trøndelag, Norway. Correlations were computed for 23,936 pairs of spouses, 43,586 pairs of parent and offspring, 19, 151 pairs of siblings, 1,251 pairs of grandparents‐grandchildren, 1,146 pairs of biological uncles/aunts‐nephews/nieces (avuncular), 801 non‐biological avuncular pairs, 169 pairs of same‐sex twins, and smaller groups of other types of relationships. Spouse correlations of 0.08 and 0.09 were approximately constant or slightly decreasing with marital duration. The correlation values for SBP and DBP were approximately 0.16 for parents‐offspring, 0.19 to 0.23 for same‐sex siblings with similar values for DZ twins, 0.19 and 0.16 for opposite‐sex siblings, 0.52 and 0.43 for MZ twins, and close to zero for most of the second‐order relationships. Genetic additive variance was estimated at 0.29 and genetic dominance variance at 0.18 with the best model for SBP. The corresponding estimates from the best models for DBP were 0.29 or lower and 0.22 or lower, the sum not exceeding 0.35. There was evidence of a moderate effect of environmental factors shared by same‐sex siblings and twins (for DBP), but no cultural transmission, and whether or not adult relatives live together does not affect familial resemblance for BP. The data did not permit a very precise resolution of the relative magnitude of genetic dominance and sibling effects. The correlation structure did not show sex‐specific genetic effects. © 1992 Wiley‐Liss, Inc.
Two‐locus mitochondrial and nuclear gene models for mitochondrial disorders
Authors: Bu Xiangdong , Yang Hui‐ying , Shohat Mordechai , Rotter Jerome I. , Vogler G. P.
Published: June 2005

Stimulated by a large pedigree with a cochlear form of deafness, for which we considered a two‐locus mitochondrial and nuclear gene model, we have extended the classic methods of segregation analysis to these classes of two‐locus disorders. Based on the unique maternal transmission pattern of the mitochondria, we demonstrate that utilization of the maternal line pedigree allows us to simplify the various two‐locus mitochondrial models to ‘one nuclear locus’ models. Classifying the nuclear families into different independent groups by the mother's phenotypes allows us to estimate the nuclear gene frequency in one group and to use this estimate as the expected value to test the fitness of the model on the other group. In addition, if we restrict the analysis to specific subsets of the mating type(s), we can also test the model on specific groups of nuclear families without estimating the gene frequency. Goodness‐of‐fit tests can be performed on pooled sibship data as well as individual sibship data. These methods of analysis should assume increasing importance as more disorders with features of mitochondrial inheritance are identified. © 1992 Wiley‐Liss, Inc.
Sensitivity of transmission probabilities to paternity exclusion in segregation analysis
Authors: Bonaïti‐pellié Catherine , Poisson Nicole , Bechtel Yvette , Bechtel Pierre , Vogler G. P.
Published: June 2005

Paternity exclusions are known to be common in Western countries and are yet neglected in segregation analysis because it is almost impossible to check it systematically on a large family sample. We had the opportunity of observing the sensitivity of segregation analysis parameters to a paternity exclusion in analyzing 34 families for a simple Mendelian trait, the acetylator phenotype. We found that only one family, with proven paternity exclusion, was responsible for a strong rejection of Mendelian transmission probabilities (P≪0.001). © 1992 Wiley‐Liss, Inc.
Extended pedigree patterned covariance matrix mixed models for quantitative phenotype analysis
Authors: Schork Nicholas J. , Vogler G. P.
Published: June 2005

Overt computational constraints in the formation of mixed models for the analysis of large extended‐pedigree quantitative trait data which allow one to reliably characterize and partition sources of variation resulting from a variety sources have proven difficult to overcome. The present paper suggests that by combining a restricted patterned covariance matrix approach to modeling and partitioning the variation arising from polygenic and environmental forces with an Elston–Stewart like algorithmic approach to modeling variation resulting from a single genetic locus with large phenotypic effects one can produce a model that is at once intuitively appealing, efficient computationally, and reliable numerically. Extensions and variations of this approach are also discussed, as are some simulation and timing studies carried out in an effort to validate the accuracy and computational efficiency of the proposed methodology. © 1992 Wiley‐Liss, Inc.
Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world
Authors: Gerdes Lars Ulrik , Klausen Ib Christian , Sihm Inger , Faergeman Ole , Vogler G. P.
Published: June 2005

Apolipoprotein E (apoE) phenotypes were determined in a random sample of 466 Danish men born in 1948. The frequencies of the common alleles of the apoE gene were (with 95% confidence intervals) ϵ2 = 0.085 (0.068–0.105), ϵ3 = 0.741 (0.712–0.769), and ϵ4 = 0.174 (0.150–0.200). These frequencies were compared to findings in 45 other study populations around the world (n > 100). The Danish population was found to cluster with populations from Iceland, Norway, Iceland, Scotland, the Netherlands, Germany, France (Paris), and Caucasian populations in Canada and the USA. The compiled data further show that dissimilarities in apoE allele frequencies among Caucasian populations are comparable to dissimilarities between some Caucasian and Asian populations. Notably, the frequency of ϵ4 appears to be higher in northern regions of Europe (the Nordic countries, Scotland, Germany, and the Netherlands) than in southern regions (Switzerland, Tyrol, France [Nancy], Italy, and Spain). © 1992 Wiley‐Liss, Inc.
Genetic variation in two bone‐related proteins: Is there an association with bone mineral density or skeletal size in postmenopausal women?
Authors: Eichner J. E. , Cauley J. A. , Ferrell R. E. , Cummings S. R. , Kuller L. H. , Vogler G. P.
Published: June 2005

In an effort to determine if structural variation in proteins important in bone metabolism might influence bone mineral density (BMD) and thus be a determinant of susceptibility to osteoporosis in older women, the authors typed a group of 258 non‐Black women (age 65–90) participating in the Study of Osteoporotic Fractures (SOF) for two polymorphic bone‐related proteins, group specific component (Gc), also known as vitamin D‐binding protein, and α2HS glycoprotein (AHSG). These two proteins exhibit common structural variation in populations that can be detected by isoelectric focusing/immunoblotting of serum. An important function of Gc is the binding, solubilization, and transport of vitamin D sterols in the bloodstream while AHSG is a glycoprotein constituent of calcified cortical bone matrix. There are six common phenotypes of Gc and four of AHSG. Using Gc or AHSG phenotypes as categorical variables, statistical analyses were done to determine if bone mineral density of the proximal or distal radius or calcaneus differed by phenotype. Neither Gc nor AHSG phenotype demonstrated a statistically significant relationship with BMD at any site. Adjustments for age and degree of obesity did not substantively affect these results. Subsequent analyses to determine if phenotype of either of these proteins was associated with variables related to skeletal size showed an association of AHSG with height (P<.02). This may indicate that AHSG phenotype is related to postmenopausal loss of height, or it may be a chance statistical finding. © 1992 Wiley‐Liss, Inc.
Influence of polymorphisms for apolipoprotein B (ins/del,Xbal,EcoRI)and apolipoprotein E on serum lipids and apolipoproteins in a Javanese population
Authors: Gajra B. , Candlish J. K. , Saha N. , Heng C. K. , Soemantri A. G. , Tay J. S. H.
Published: June 2005

A total of 231 healthy subjects from a central Javanese population were investigated for the distribution of three apolipoprotein B (apo B) polymorphisms (ins/del,XbaI, andEcoRI), as well as apolipoprotein E (apo E) polymorphism in relation to serum lipid and apolipoprotein concentrations. The frequencies of the rarer alleles (del, 0.09;X+, 0.1; andR−, 0.06) were lower than have been found for some Asian and European populations. Distribution of genotypes was in Hardy‐Weinburg equilibrium for all the polymorphisms. A linkage disequilibrium was observed only between theins/delandXbaI site polymorphisms of apo B (χ42= 25.3;P< 0.001) consistent with that observed in some other population studies. No polymorphism of the apo B gene had an association with serum lipid or apolipoprotein concentrations in this population except forXabI, which appeared to be associated with serum TG (as the log transform:R2= 8.3;F= 4.8;P< 0.01). The apo E4 allele was found to be associated with significantly higher serum total cholesterol (TC) and low‐density lipoprotein cholesterol (LDLC). Apo E polymorphism explained 5.9% of the sample variance of serum LDLC (F= 5.4;P< 0.01). © 1994 Wiley‐Liss, Inc.
Survival models for developmental genetic data: Age of onset of puberty and antisocial behavior in twins
Authors: Pickles Andrew , Crouchley Robert , Simonoff Emily , Eaves Lindon , Meyer Joanne , Rutter Michael , Hewitt John , Silberg Judy
Published: June 2005

The use of survival analysis for developmental genetic data is discussed. The main requirements for models based on the decomposition of frailty distributions into shared and unshared components are outlined for the simple case of twins. Extending the earlier work of Clayton, Oakes, and Hougaard, among others, three forms of hazard model are presented, all of which can be applied to pedigree data with flexible baseline hazards without the use of numerical integration. The first two models use an additive decomposition of frailty, with either gamma or positive stable law distributed (PSL) components. The third model previously described by Hougaard involves a multiplicative PSL decomposition. The models are applied to data on the onset of puberty in male twins and illustrate the importance of correct specification of the baseline hazard for correct inference about genetic effects. The difficulty of assessing model specification using information only on the margins is also noted. Overall, the new model with additive PSL components appeared to fit these data best. A second application illustrates the use of a time‐varying covariate in examining the impact of puberty on the onset of conduct disorder symptomotology. © 1994 Wiley‐Liss, Inc.
Robust genetic linkage analysis based on a score test of homogeneity: The weighted pairwise correlation statistic
Authors: Commenges D.
Published: June 2005

In testing genetic linkage using large or complex pedigrees, robust methods may be preferred to the Lod‐score method. The affected‐pedigree‐member method is robust but does not use the information available in nonaffected subjects, which results in a loss of power. We propose a new test of genetic linkage based on a score test of homogeneity derived from a random effect model. The statistic is simple and uses only pairs of subjects. In contrast with the affected‐pedigree‐method, it uses all the available pairs and does not depend on the marker alleles frequencies. A rank version of this weighted pairwise correlation statistic is proposed, its exact first and second moment derived. We show that for age‐dependent diseases, it provides a simple nonparametric test. © 1994 Wiley‐Liss, Inc.
Polymorphism in the promoter region of the apolipoprotein AI gene associated with differences in apolipoprotein AI levels: The European Atherosclerosis Research Study
Authors: Talmud Philippa J. , Ye Shu , Humphries Steve E. ,   On Behalf of The Ears Group
Published: June 2005

The effect associated with the substitution of adenine (A) for guanidine (G) in the promoter region of the apolipoprotein AI gene (−75 bp) with plasma apo AI and high‐density lipoprotein (HDL) levels was investigated in the European Atherosclerosis Research Study (EARS). This is a study of healthy offspring (cases) of fathers who had suffered premature myocardial infarction (MI) before age 55 years (n = 565) and age‐ and sex‐matched controls (n = 1,078) from 12 European countries, divided into 5 regions based on geography and language. The frequency of the polymorphism was not significantly different among the regions and the relative frequency of the rare A allele was similar in cases and controls (0.159 vs. 0.142) combining data from all regions. Individuals with one or more A allele had significantly higher plasma apo AI levels (P < 0.05) than individuals homozygous for the G allele. This effect was consistent in all regions. The data were analyzed separately in males and females. In females, those with one or more A allele had significantly higher apo AI levels (P = 0.05) than individuals homozygous for the G allele, and this raising effect of the A allele was greater in cases than controls for both apo AI (5.23% vs. 1.56%) and HDL (4.48% vs. 1.89%). In males, the A allele was associated with higher levels of apo AI and HDL, but the effect was much smaller and the differences did not reach statistical significance. In the females, where the effect of the A allele was strongest, the effect on apo AI associated with genotype was evident in non‐smokers, and individuals with one or two A alleles had 3.6% higher apo AI and 3.14% higher HDL levels than individuals homozygous for the G allele. However, in the female smokers the raising effect of the A allele was greatly reduced (0.56%). Thus genetic variation in the promoter region of the apo AI gene is associated with differences in apo AI and HDL levels in healthy individuals throughout Europe, but the effect is modulated by gender, environmental factors such as smoking, and a family history of MI.
Commingling analysis of memory performance in elderly men
Authors: Palmer Christina G. S. , Wolkenstein Bonnie H. , La Rue Asenath , Swan Gary E. , Smalley Susan L.
Published: June 2005

Smalley et al. [(1992) Genet Epidemiol 9:333–345] found evidence of a mixture of two distributions in memory performance among offspring of patients with dementia of the Alzheimer type (DAT), suggesting that these groups reflect genotypic subgroups of carriers and non‐carriers of a putative DAT gene. One prediction of this hypothesis is that, in the general population, two distributions of memory performance are present, with a smaller proportion of subjects in the low‐scoring cluster than that found among the offspring sample, but similar to the prevalence of DAT in the elderly community‐at‐large. Memory performance was investigated in a large sample of normal elderly males (N = 1,149; mean age = 71.4 ± 4.7 years) to test this hypothesis. Commingling analyses of performance on the Benton visual retention test demonstrated significant negative skewness in the distribution of memory performance, requiring a transformation to fit a single normal distribution. In the absence of a transformation, two distributions fit better than one, with 6% of subjects falling into a “low”‐scoring cluster. These findings are consistent with the hypothesis that memory performance may represent a premorbid or morbid difference in those who go on to develop, or currently have, DAT, possibly allowing identification of at‐risk carriers of a putative single major gene for DAT. © 1994 Wiley‐Liss, Inc.
Feasibility of half‐sibling designs for detecting a genetic component to a disease
Authors: Tierney Camlin , Merikangas Kathleen R. , Risch Neil
Published: June 2005

In genetic epidemiology, adoption and twin study designs are the most commonly used designs to identify genetic and common environmental components underlying familial aggregation. Other fixed family set designs such as a half‐sibling design can also be applied to test the same hypotheses. The feasibility of half‐sibling designs for detecting a genetic (single‐locus or multifactorial) source of familial aggregation of a disease is studied and is compared to both adoption and twin study designs. Results are presented for two types of design where the sampling units are relative pairs reared apart (I) or reared together (II). Although they generally require more observations to achieve the same power, designs involving half‐siblings may be more feasible in situations where there is greater availability of these relatives. © 1994 Wiley‐Liss, Inc.
Interaction between genetic and environmental risk factors for Alzheimer's disease: A reanalysis of case‐control studies
Authors: Van Duijn C. M. , Clayton D. G. , Chandra V. , Fratiglioni L. , Graves A. B. , Heyman A. , Jorm A. F. , Kokmen E. , Kondo K. , Mortimer J. A. , Rocca W. A. , Shalat S. L. , Soininen H. , Hofman A. ,   EURODEM Risk Factors Research Group
Published: June 2005

To study the interaction among genetic and environmental risk factors, a reanalysis of case‐control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising a total of 814 AD patients and 894 control subjects. When comparing those with a positive and negative family history of dementia, similar odds ratio were found for late maternal age [1.7; 95% confidence interval (0.6–4.8) vs. 2.0 (1.1–3.5)], head trauma [1.7 (0.7–4.2) vs. 1.9 (1.1–3.2)], and history of depression [2.0 (0.2–19.8) vs. 2.1 (0.8–1.7)]. This suggests a model in which these risk factors increase the risk for AD independent of family history of dementia. Among those with a positive family history of dementia, the odds ratios for family history of Down's syndrome [4.2 (0.9–20.0))] and of Parkinson's disease [3.3 (0.4–28.2)] tended to be higher than among those with a negative family history of dementia [2.6 (0.8–8.5) and 2.4 (0.8–7.0), respectively]. However, for both disorders the difference in odds ratio was not statistically significant. For history of cigarette smoking, there was no association to AD for those with no first degree relatives with dementia and an inverse relation with AD for those with a positive family history. Although in all analyses, family history of dementia remained significantly associated with AD in the absence of other factors, the odds ratio associated with family history of dementia tended to be lower for those with a positive smoking history, particularly for those with two or more affected relatives. These findings suggest that smoking may interact specifically with a genetically determined process. © 1994 Wiley‐Liss, Inc.
Complex segregation analysis of leprosy in Southern Vietnam
Authors: Abel Laurent , Lap Vu Dinh , Oberti Jean , Van Thuc Nguyen , Van Cua Van , Guilloud‐Bataille Michel , Schurr Erwin , Lagrange Philippe H.
Published: June 2005

To investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990) Genet Epidemiol 7:391–407], which accounted for variable age of onset and time‐dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis. © Wiley‐Liss, Inc.
Phenotypic assortative mating in segregation analysis
Authors: Hasstedt Sandra J.
Published: June 2005

A model of phenotypic assortative mating was developed for application in segregation analysis. The model assumed a constant spouse correlation across the range of a quantitative trait or the liability to a discrete trait. Four traits were analyzed to evaluate: (1) the feasibility of applying likelihood analysis to pedigree data in order to distinguish between assortative mating and shared environmental effects as the source of spouse correlation; and (2) the impact on segregation analysis of the failure to account for either assortative mating or shared environmental effects, as appropriate. Height ratio (the ratio of sitting to standing height) and eye color comprised the traits for which the observed spouse correlation reflected assortative mating; serum cholesterol and peptic ulcers (with genotypes defined by the ABO blood group) comprised the traits for which the observed spouse correlation reflected shared environmental effects. For all four traits the test statistics agreed with the known cause of spouse correlation; however, significance was not attained for height ratio or serum cholesterol. The ability to distinguish between the causes of spouse correlation in pedigree data presumably depends on trait and sample characteristics which remain to be delineated. Despite significant spouse correlation, its omission from the segregation analysis model did not undermine the inference of major locus inheritance for any of the four traits. However, the lack of an impact for these traits does not preclude an impact for other traits of ignoring the appropriate spouse correlation in segregation analysis. © 1995 Wiley‐Liss, Inc.
Segregation analysis of plasma lipoprotein(a) levels in pedigrees with molecularly defined familial hypercholesterolemia
Authors: Friedlander Yechiel , Leitersdorf Eran
Published: June 2005

The role of genetic and environmental factors in determining the variability in plasma lipoprotein(a) [Lp(a)] levels was investigated in 220 members of 14 families with familial hypercholesterolemia (FH) whose plasma Lp(a) levels were previously reported [Leitersdorf et al. (1991) J Lipid Res 32:1513–1519]. One hundred four subjects harbored a mutant low density lipoprotein (LDL) receptor allele as confirmed by the identification of the specific mutations in addition to the haplo‐type analysis reported before. Four different mutant alleles were identified, each in a defined genetic group—Druze, Christian‐Arabs, Ashkenazi, and Sephardic Jews. Sex‐ and age‐adjusted mean plasma Lp(a) levels were significantly higher in FH family members (34.0 mg/dl) than in non‐FH family members (21.1 mg/dl). Lp(a) levels were further adjusted for lipid levels and apo(a) isoforms. A mixture of two normal distributions fitted the adjusted Lp(a) levels better than did a single normal distribution. Segregation analysis indicated that a major effect of a non‐transmitted environmental factor explained the mixture of distributions in addition to polygenic loci which influenced Lp(a) levels within each distribution. The major environmental factor and the polygenic loci accounted for 45% and 20% of the adjusted Lp(a) variation, respectively. Furthermore, sex, age, lipid levels, apo(a) isoform, the major environmental effect, and the unmeasured polygenes could account for 80% of the unadjusted variation of plasma Lp(a) in these families. © 1995 Wiley‐Liss, Inc.
Guess LOD approach: Sufficient conditions for robustness
Authors: Williamson John A. , Amos Christopher I.
Published: June 2005

Analysis of genetic linkage between a disease and a marker locus requires specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecification of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecifying the genetic model for disease inheritance does not lead to excess false‐positive evidence for genetic linkage provided the genetic marker alleles of all pedigree members are known, or can be inferred without bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the genetic model for the marker locus may be incorrect. We provide sufficient conditions for the asymptotic unbiased estimation of the recombination fraction under the null hypothesis of no linkage, and also conditions for the limiting distribution of the likelihood ratio test for no linkage to be chi‐squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic model is misspecified. Among those situations under which an excess of false‐positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele frequencies. We show that in most cases false‐positive evidence for genetic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance. © 1995 Wiley‐Liss, Inc.
General purpose model and a computer program for combined segregation and path analysis (SEGPATH): Automatically creating computer programs from symbolic language model specifications
Authors: Province Michael A. , Rao D. C.
Published: June 2005

A general purpose model and a flexible computer program, called SEGPATH, have been developed to assist in the creation and implementation of a variety of genetic epidemiological models. SEGPATH is a computer program which can be used to generate programs to implement linear models for pedigree data, based upon a flexible, model‐specification syntax. SEGPATH models can perform segregation analysis, path analysis, or combined segregation and path analysis using any user‐specified path model and can be structured to analyze any number of multivariate phenotypes, environmental indices, and/or measured covariate fixed effects (including measured genotypes). Population heterogeneity models, repeated‐measures models, longitudinal models, auto‐regressive models, developmental models, and gene‐by‐environment interaction models can all be created under SEGPATH. Pedigree structures can be defined to be arbitrarily complex, and the data analyzed with programs generated by SEGPATH can have any missing value structure, with entire individuals missing, or missing on one or more measurements. Corrections for ascertainment can be done on a vector of phenotypes and/or other measures. Because the model specification syntax is general, SEGPATH can also be used in non‐genetic applications where there is a hierarchical structure, such as longitudinal, repeated‐measures, time series, or nested models. A variety of applications are demonstrated. © 1995 Wiley‐Liss, Inc.
Using loss of heterozygosity data in affected pedigree member linkage tests
Authors: Lustbader Edward D. , Rebbeck Timothy R. , Buetow Kenneth H.
Published: June 2005

Linkage analysis can be used to test the hypothesis that a marker locus of known location segregates independently from a presumed disease gene. One way to test this hypothesis is to measure the similarity of marker alleles among pairs of relatives affected with the disease. When the disease under consideration is cancer, it is possible to take advantage of the marker alleles in tumors to revise the similarity measure obtained from the observations made in constitutional tissue. Only cancers that arise through the model of recessive oncogenesis are amenable to this revised analysis. This model postulates that cancer is caused by somatic genetic changes which result in the loss of one or both copies of a normal allele at a tumor suppressor locus. If an individual's inherited genotype is heterozygous at the marker locus, the model of recessive oncogenesis suggests that we may observe loss of constitutional heterozygosity at the marker locus in the tumor. In this report, we show how to incorporate this loss of heterozygosity data into affected pedigree member linkage tests. The revised procedure is illustrated using data obtained from relatives with breast cancer. Substantial improvement in the power to reject the different chromosome hypothesis is obtained when loss of heterozygosity is observed in multiple relatives with the same marker alleles retained in the tumors. ©1995 Wiley‐Liss, Inc.
Simulation study comparing interval estimates for the recombination fraction
Authors: Nemesure Barbara Berger , Greenberg David A. , Mendell Nancy R.
Published: June 2005

Three interval estimation procedures were evaluated to determine the method which provides the most accurate estimates for the recombination fraction, θ. The lod–0.83 support interval, the jackknife confidence interval, and the confidence interval based on estimated asymptotic standard error were compared by calculating the coverage probabilities of each. Family data that were simulated under the model of a single fully penetrant, dominant disease locus at some distance, θ, from fully informative matings were used. Comparisons were based on 1,000 random samples of size 20, 60, and 100 families. In addition, a methodology for obtaining prediction intervals for θ was developed. This procedure is of practical use and does not require asymptotic assumptions based on large sample theory. The results provide an a priori idea about precision of the estimates, as well as empirical interval estimates of θ. Graphs of the authors' Monte Carlo intervals are presented for these simulations. Investigators studying different traits, however, could condition specifically on the family structure and distribution of the disease they are investigating and obtain similar graphs. ©1995 Wiley‐Liss, Inc.
Angiotensin‐converting enzyme genotypes in the high‐ and low‐risk area for coronary heart disease in Finland
Authors: Perola Markus , Sajantila Antti , Sarti Cinzia , Stengård Jari , Tamminen Markku , Puska Pekka , Huttunen Jussi , Tuomilehto Jaakko , Peltonen Leena
Published: June 2005

The deletion/deletion genotype of the insertion (I)/deletion (D) polymorphism of the angiotensin‐converting enzyme (ACE) gene has been suggested to be a risk factor for myocardial infarction (MI). The objective of this study was to evaluate whether genotypic distributions of the I/D polymorphism of the ACE gene are different between individuals from high‐risk and low‐risk areas for coronary heart disease in the genetically isolated population of Finland and to assess the impact of this genetic risk factor by comparing individuals with different parental histories of MI. Representative population‐based samples of middle‐aged men (n = 363) and women (n = 358) from two areas of Finland were used. The area had a borderline significant effect on the prevalence of the genotype DD (β = 0.35, SE = 0.16, χ2 = 4.70, df = 1, P = 0.03), the DD genotype being more prevalent in eastern Finland (the high‐risk area). The II genotype was more prevalent in women with parental history of MI, so we could not replicate the previous findings of the risk‐increasing effect of DD genotype in this sample. Although the observed difference in the ACE DD genotype between the high‐risk and low‐risk areas for coronary heart disease might represent one of the genetic factors contributing to the difference in risk of coronary heart disease between eastern and southwestern Finland, the data emphasize the fact that also other risk factors, including other genes, contribute to this difference and the high incidence of MI in Finland. ©1995 Wiley‐Liss, Inc.
Variation in HLA‐associated risks of childhood insulin‐dependent diabetes in the finnish population: I. Allele effects at A, B, and DR Loci
Authors: Langholz Bryan , Tuomilento‐Wolf Eva , Thomas Duncan , Pitkäniemi Janne , Tuomilehto Jaakko ,   DiMe Study Group
Published: June 2005

Variation in the risk of insulin‐dependent diabetes mellitus (IDDM) across alleles at HLA‐A, B, and DR loci was investigated in a population‐based study of 801 families of children with newly diagnosed IDDM in Finland nationwide. Parallel analyses assessed the relative frequencies of alleles in IDDM children compared with age‐matched sibling controls and with the four possible genotypes which could have been inherited from the parents. The joint effects of DR3 and DR4 alleles were investigated under dominant, recessive, and additive models of gene expression. The additive model gave the best fit, though the relative risk for DR4 homozygotes was smaller than predicted. To investigate other alleles, we fitted the standard multiplicative model for alleles at each locus. After controlling for the correlation among alleles, significantly elevated risks were found for B13, DR3, DR4, and DR14. Subjects with these alleles have more than twice the risk of IDDM as those without. Alleles A24 and B62 incurred relative risks between one and two. DR2 and DR5 were significantly negatively associated with IDDM, incurring less than half the risk. These findings support an independent role of class I antigens in the etiology of IDDM. © 1995 Wiley‐Liss, Inc.
Apolipoprotein B gene DNA polymorphisms (EcoRI and MspI) and serum lipid levels in the serbian healthy population: Interaction of rare alleles and smoking and cholesterol levels
Authors: Glišić S. , Savić I. , Alavantić D.
Published: June 2005

The frequency of restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene, detected by EcoRI and MspI, and their influence on serum lipids were studied in a total of 239 healthy subjects from the Belgrade area. The influence of interaction between different genotypes and smoking was also studied. The relative frequency of both rare R2 and M2 alleles (lacking the cutting site) was similar to that reported in other groups of Caucasians (0.16 and 0.11, respectively). No association was observed between the apo B genotypes and serum lipid levels adjusted for age, body mass index, and blood pressure either in the whole sample or in either women or men. When smokers and non‐smokers were considered separately, smoking had a significant impact on total cholesterol variability in all individuals with genotype M1M2 and high density lipoprotein (HDL) cholesterol variability in women with genotype R1R2. The presence of the rare alleles of these two polymorphisms in smokers was associated with lower lipid levels in the whole sample and in both women and men analyzed separately, except for an increase of HDL cholesterol level in male smokers, heterozygous for EcoRI polymorphism (R1R2). ©1995 Wiley‐Liss, Inc.
Genome scan for association and linkage
Authors: Holmans P. , McGuffin P. , Clayton D.
Published: June 2005

In this paper, a genome search is performed on the GAW Problem 1 data, in an attempt to determine which, if any, of the marker loci are associated and/or linked with the disease. Since there was no clear indication from the data of the likely mode of inheritance, methods were used which did not require such assumptions to be made. A two‐stage procedure was used to test for association. Firstly a standard unmatched case‐control test was applied to all the loci. The family‐based method of Self et al. [1991] was then applied to those loci which gave a positive result in the first stage. This procedure correctly detected loci 1 and 2, and that disease risk was increased for homozygote carriers of the disease allele at each locus, although a false positive result was also found. The affected sib pair method of Holmans [1993] was also applied to the data, although the sample contained far too few sib‐pairs for such an analysis to be effective. This analysis failed to find any of the disease loci. ©1995 Wiley‐Liss, Inc.
The TDT reveals linkage and linkage disequilibrium in a rare disease
Authors: McGinnis Ralph E. , Ewens Warren J. , Spielman Richard S.
Published: June 2005

We used the TDT as the basis for our analysis of data from Problem 1 of GAW9. Among the 360 marker loci on six chromosomes, we searched for any that might show both linkage and allelic association with the disease. We applied the TDT to each allele at every marker locus and found strong evidence for linkage in two regions: one on chromosome 1, another on chromosome 5. ©1995 Wiley‐Liss, Inc.
Evaluation of screening strategies to detect an oligogenic disease
Authors: Rogus John J. , Haines Jonathan L.
Published: June 2005

Using data simulated to reflect an oligogenic disease, we evaluated screening strategies based on lod‐score and weighted pairwise correlation (WPC) analysis with respect to their ability to efficiently identify regions near disease loci. Lod‐score analysis was done twice, once assuming a near‐recessive mode of inheritance with a high penetrance and again assuming a semidominant mode of inheritance with lower penetrance. Under the near‐recessive model, no disease loci were correctly identified, while there was one false positive result. Under the semidominant model, D1G31 was correctly identified, and there were two false positive results. Due to the lack of highly informative families and possible sensitivity to parameter misspecification, this poor performance was not unexpected. WPC, on the other hand, is assumption‐free and thus potentially more powerful than a misspecified parametric model, but almost certainly less powerful than a well‐specified parametric model. Using WPC modified to handle binary phenotypes with no age‐of‐onset, we found results closely resembling those under the semidominant model, although no markers near disease loci exceeded the theoretical critical value for WPC. © 1995 Wiley‐Liss, Inc.
Precision of marker heterozygosity estimates
Authors: Shugart Yin Y.
Published: June 2005

Sample sizes may greatly affect the accuracy of estimates of marker heterozygosities. Therefore, indicating the precision of these estimates is strongly recommended. A computer program HETMAX was written and used to obtain unbiased estimates of heterozygosity, their standard errors and unit support intervals, based on a subset of GAW9 data. The accuracy of the estimates and the associated sample sizes are presented. © 1995 Wiley‐Liss, Inc.

Sample sizes may greatly affect the accuracy of estimates of marker heterozygosities. Therefore, indicating the precision of these estimates is strongly recommended. A computer program HETMAX was written and used to obtain unbiased estimates of heterozygosity, their standard errors and unit support intervals, based on a subset of GAW9 data. The accuracy of the estimates and the associated sample sizes are presented. © 1995 Wiley‐Liss, Inc.
Sib‐based detection of QTLs
Authors: Suarez Brian K. , Hampe Carol L. , O'rourke Dennis , Van Eerdewegh Paul , Reich Theodore
Published: June 2005

Association and transmission/nontransmission analyses were used in a split sample design to identify disease susceptibility alleles at two loci. Sib‐pair analysis on various subsets of the data identified an additional four regions that yielded signals of disease predisposing quantitative trait loci (QTLs). Three of these four regions represented Type I errors. A new simulation indicates that a multiplex sampling strategy would substantially improve QTL detection for this oligogenic transmission model. © 1995 Wiley‐Liss, Inc.
Measuring gene‐disease association using a general pair method
Authors: Ward Patrick J. , Bonaïti‐Pellié Catherine
Published: June 2005

The general‐pair‐method (GPM) was applied to the analysis of the Problem 1 data set. GPM is a nonparametric, identity‐by‐state method for associating variation at a chromosomal locus with disease status. It can accommodate information from all pairs of individuals across any degree of genetic relatedness, including genetically unrelated individuals, within a single test statistic. Pairwise contrasts between members of different pedigrees, including “control” pedigrees containing no affected individuals, can therefore be exploited in order to increase the power of the test statistic. Such a strategy makes sense within the context of a candidate gene (direct association) study, where the alleles or genotypes of high disease risk are assumed to be the same ones within all families. Applied to the Problem 1 data set in this way, the GPM successfully identified the effect on disease status of locus 31 on chromosome 1, and of locus 23 on chromosome 5. The observed strength of gene‐disease association at the other chromosomal loci was compatible with the null hypothesis. © 1995 Wiley‐Liss, Inc.
Simulation of a common oligogenic disease with quantitative risk factors. GAW9 problem 2: The answers
Authors: MacCluer Jean W. , Blangero John , Dyer Thomas D. , Kammerer Candace M.
Published: June 2005

For Problem 2, simulated family data were provided for a common oligogenic disease that was defined by imposing a threshold, T, on a quantitative trait, Q1. Every individual with a value of Q1 > T (where T = 87.5) was defined as affected. Participants were told that three other quantitative traits (Q2, Q3, and Q4) and an environmental factor (EF) also were thought to be associated with the disease as intervening variables, and that 12 candidate loci (C1 ‐ C12) were postulated to influence traits associated with the disease. The tasks for GAW9 were to characterize the genetic and environmental contribution to Q1 (and the disease), Q2, Q3, and Q4, and to localize any single genes that had detectable effects. © 1995 Wiley‐Liss, Inc.