bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic variation at the apolipoprotein gene loci contribute to response of plasma lipids to dietary change
Authors: Xu C.‐F. , Boerwinkle E. , Tikkanen M. J. , Huttunen J. K. , Humphries S. E. , Talmud P. J. , Rao D. C.
Published: June 2005

Dietary intervention studies (from a low polyunsaturated/saturated fatty acid ratio P/S diet to a high P/S diet), carried out on a group of healthy individuals from North Karelia, Eastern Finland between 1981–1984, provided evidence that there may be a genetic component contributing to variation in response to dietary change. We have resampled blood from 107 individuals involved in the original studies and used Restriction Fragment Length Polymorphisms (RFLPs) to study the genetic contribution of variation at a number of candidate gene loci to the response to dietary change. The genes investigated in this study were the apolipoprotein (apo) genes: apo B, apo AII, apo E (protein polymorphism), apo AI‐CIII‐AIV gene cluster, and the LDL‐receptor gene.

On the basal diet the major effect of genotype on lipid traits was due to variation at the apo E gene locus; this protein polymorphism explained 14.6% of the phenotypic variance in LDL cholesterol levels and 12.7% of the phenotypic variance in total cholesterol levels. When switched to low fat high P/S diet, these effects of variation at the apo E gene locus on the phenotypic variation of LDL and total cholesterol levels disappeared. The major effect on the response to dietary change, Δ, was seen on the difference in apo AI levels mediated by variation at the apo B gene locus (MspI RFLP) explaining 6.3% of the phenotypic variance in apo AI change. For the RFLPs of the apo AI‐CII‐AIV gene cluster, small but not significant differences on Δ were found. Our results indicate that within the limits of the candidate genes studied, the major effects in response to dietary change was on apo AI levels mediated through variation at the apo B gene locus.
Search for faster methods of fitting the regressive models to quantitative traits
Authors: Demenais Florence M. , Murigande Charles , Bonney George E. , Rao D. C.
Published: June 2005

The regressive models describe familial patterns of dependence of quantitative measures by specifying regression relationships among a person's phenotype and genotype and the phenotypes and genotypes of antecedents. When the number of sibs in the pattern of dependence increases, as in the class D regressive model, computation of the likelihood becomes time consuming, since the Elston‐Stewart algorithm cannot be used generally. On the other hand, the simpler class A regressive model, which imposes a restriction on the sib‐sib correlation, may lead to inference of a spurious major gene, as already observed in some instances. A simulation study is performed to explore the robustness of class A model with respect to false inference of a major gene and to search for faster methods of computing the likelihood under class D model. The class A model is not robust against the presence of a sib‐sib correlation exceeding that specified by the model, unless tests on transmission probabilities are performed carefully: false detection of a major gene is reduced from a number of 26–30 to between 0 and 4 data sets out of 30 replicates after testing both the Mendelian transmission and the absence of transmission of a major effect against the general transmission model. Among various approximations of the likelihood formulation of the class D model, approximations 6 and 8 are found to work appropriately in terms of both the estimation of all parameters and hypothesis testing, for each generating model. These approximations lessen the computer time by allowing use of the Elston‐Stewart algorithm.
Family history of ischemic heart disease with respect to mean twin‐pair cholesterol and subsequent ischemic heart disease in the NHLBI twin study
Authors: Reed Terry , Fabsitz Richard R. , Quiroga Jose
Published: June 2005

This study examines the independent and interactive effects of family history scores (FHxS) for the prevalence of ischemic heart disease with plasma lipids and subsequent morbidity and mortality from ischemic heart disease. FHxS were calculated for 514 sets of middle aged male twins who participated in the entry examination of the NHLBI Veteran twin study in 1969–1973. Comparison of the FHxS with the level of plasma total cholesterol and HDL cholesterol (HDLc) paralleled earlier reported findings in young adults; individuals with high total cholesterol in two exams 8–12 years apart had significantly (P < .01) higher FHxS. The same relationship was noted when using the mean twin‐pair cholesterol level at the initial exam when the twins were in their 40s. Using the pair means over two exams as the cotwins aged into their 50s, the association of FHxS with total cholesterol declined and pairs with HDLc persistently in the highest quintile at both exams had significantly (P < .01) lower FHxS. The changes in the pattern of association of lipid fractions with FHxS with age parallel the reported age decline of total cholesterol as a risk factor for heart disease. Assessment of ischemic heart disease events up to January 1988 revealed a highly significant association (P < .0001) of later ischemic heart disease events with FHxS. At each level of lipid categorization pairs who later had events had higher FHxS than those without any subsequent heart disease; these differences were significant in all but the low risk lipid groups (low total cholesterol, high HDLc, and low total cholesterol/HDLc ratio). We conclude that FHxS is related to total cholesterol and HDLc but also is an independent predictor of subsequent ischemic heart disease after 14–18 years of follow‐up.
Linkage analysis assuming a single‐locus mode of inheritance for traits determined by two loci: Inferring mode of inheritance and estimating penetrance
Authors: Greenberg David A. , Rao D. C.
Published: June 2005

What happens to the results of linkage analysis when one assumes that a disease results from a single genetic locus with reduced penetrance when the actual cause is two epistatically interacting loci? We wanted to (1) determine whether assuming the correct mode of inheritance at the linked locus leads to a higher lod score than assuming the incorrect mode of inheritance irrespective of penetrance assumptions and (2) determine whether it is possible to estimate the apparent penetrance due to the second, unlinked locus from the linkage data. Linkage data were simulated under three different two‐locus models. Different “penetrances” were simulated by using different disease allele frequencies at the unlinked locus. Data were then analyzed assuming a single locus with reduced penetrance. The maximum lod score was maximized with respect to penetrance (LVP curves).

We found that if there were enough data, assuming the correct (i.e., generating) mode of inheritance at the linked locus always led to a higher lod score than assuming the incorrect mode of inheritance no matter what the penetrance assumption. In contrast to the case where reduced penetrance is due to random factors, the estimate of the apparent penetrance (the “penetrance” due to the second locus) was biased, thus making any estimation of the gene frequency at the second locus doubtful. The ability to detect linkage was apparently not affected when the effects of the second locus were treated as random reduced penetrance. The results suggest that analyzing the data under the assumption of a single‐locus model with reduced penetrance rather than a two‐locus model will not substantially decrease the ability to establish linkage nor will it affect determining the mode of inheritance at the linked locus from the linkage data.
Efficient computation of patterned covariance matrix mixed models in quantitative segregation analysis
Authors: Schork Nicholas , Vogler G. P. , Rao D. C.
Published: June 2005

The use of patterned covariance matrices in forming pedigree‐based mixed models for quantitative traits is discussed. It is suggested that patterned covariance matrix models provide intuitive, theoretically appealing, and flexible genetic modeling devices for pedigree data. It is suggested further that the very great computational burden assumed in the implementation of covariance matrix‐dependent mixed models can be overcome through the use of recent architectural breakthroughs in computing machinery. A brief and nontechnical overview of these architectures is offered, as are numerical and timing studies on various aspects of their use in evaluating mixed models. As the kinds of computers discussed in this paper are becoming more prevalent and easier to access and use, it is emphasized that it behooves geneticists to consider their use to combat needless approximation and time constraints necessitated by smaller, scalar computation oriented, machines.
Power of the admixture test to detect genetic heterogeneity
Authors: Narod Steven A. , Vogler G. P.
Published: June 2005

Several dominant genetic diseases which appear to be homogeneous are the expression of genetic mutations at several loci. The power to detect linkage by likelihood methods is diminished for heterogeneous, as compared to genetically homogeneous, disorders. Using a simulation approach and two pedigrees typical of those available for the study of a dominant disease (with expected lod scores of 0.43 and 1.00 at θ = 0.05 and PIC = .59), I have evaluated the power to detect genetic heterogeneity by using the admixture test. Linkage power was determined by varying the number of families available for study, the recombination fraction (θ), the informativity of the hypothetical marker, and the proportion of linked families, α. For moderate and small values of α it is feasible to detect genetic heterogeneity once linkage has been established; rarely will it be possible to detect linkage and heterogeneity simultaneously given a limited number of small or moderate pedigrees.
Informativeness of twin‐nuclear family and nuclear family designs for segregation analysis
Authors: Duffy David L. , Eaves Lindon J. , Vogler G. P.
Published: June 2005

This brief note examines the precision of segregation parameter estimates from both twin‐nuclear family and conventional nuclear family designs. The program MENDEL was used to derive expected frequencies of different family patterns of affectation (with fixed sibship size) under various single gene models, and then to estimate the standard errors (and information) associated with gene frequency and penetrance values at given sample sizes. As might be expected, a 2‐ to 5‐fold increase in relative efficiency was found for the same family size if families included an MZ twin pair among their offspring. The methods used allow convenient calculation of expected informativeness of a given study design.
Lack of evidence for linkage between low‐density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia
Authors: Austin Melissa A. , Wijsman Ellen , Guo Sunwei , Krauss Ronald M. , Brunzell John D. , Deeb Samir , Vogler G. P.
Published: June 2005

Low‐density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = −13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.
Apolipoprotein E polymorphism and plasma lipid, lipoprotein, and apolipoprotein levels in Italian children
Authors: Xu Chun‐Fang , Talmud Philippa J. , Angelico Francesco , Ben Maria Del , Savill John , Humphries Steve E. , Vogler G. P.
Published: June 2005

We have investigated the effect of apolipoprotein (apo) E polymorphism on serum lipid, lipoprotein, and apolipoprotein levels in a sample of 195 children, aged 8–11 years, from Sezze, Central Italy. The relative frequencies of e2, e3, and e4 alleles were 0.062, 0.867, and 0.072, respectively. Variation at the apo E gene locus explained 5.1% of the sample variance in serum total cholesterol levels, 7.6% in low‐density lipoprotein (LDL) cholesterol levels, 7.3% in apo B levels, and 14.1% in high‐density lipoprotein‐apo E (HDL‐E) levels. The effect of the e2 allele was to lower levels of total cholesterol, LDL‐cholesterol, and apo B and to raise levels of HDL‐E, while the effect of the e4 allele was the opposite. Variation at the apo E gene locus was not associated with differences in serum triglyceride, HDL‐cholesterol, or apo AI levels. The effects of common apo E polymorphisms and genetic variation associated with the PvuII RFLP of the apo B gene on serum apo B levels were additive, explaining 11.3% of the phenotypic variance in this sample. When the effect of apo E polymorphism on serum lipid traits was estimated in boys and girls separately, variation at the apo E gene locus explained 10.4, 13.3, 13.3, and 13.5% of the phenotypic variance in serum total cholesterol, LDL‐cholesterol, apo B, and HDL‐E levels, respectively, in boys, while in girls only the effect on HDL‐E levels (19.3%) reached statistical significance. This study has demonstrated that genetic variations at the apo E locus contribute to the determination of serum lipid, lipoprotein, and apolipoprotein levels in youths and that the effects are gender specific.
Extensions to methods of sib‐pair linkage analyses
Authors: Flanders W. Dana , Khoury Muin J. , Vogler G. P.
Published: June 2005

Sib‐pair methods provide simple, robust, easily implemented ways to screen for linkage between a marker locus and a suspected disease susceptibility locus. The basic analysis reflects the idea that, in the presence of linkage, siblings who share more alleles at the marker locus should also tend to be concordant for disease. Available sib‐pair methods do not lead directly to estimates of risk associated with nongenetic factors, may not account for a variable age‐at‐onset, or may require that the age‐at‐onset distribution be known. In this paper, we propose a method for sib‐pair linkage analyses that allows for a variable age‐at‐onset using a logistic model, easily allows modelling of nongenetic factors, reflects the correlation of sibs within a sibship, and allows for nonzero risk in those without the susceptibility genotype. Based on a limited number of simulations, the method has as good or better power than another recently described method that also allows for a variable age‐at‐onset.
Are offspring of women with hereditary hematologic disorders at increased risk of congenital cardiovascular malformations?
Authors: Khoury Muin J. , Waters Grady D. , Martin M. Louise , Edmonds Larry D. , Vogler G. P.
Published: June 2005

Hereditary hematologic disorders (HHD) have been reported in excess among infants and families of infants with congenital cardiovascular malformations (CCM) compared with controls, suggesting possible common pathogenetic mechanisms. It is plausible that hemodynamic changes during pregnancy associated with HHD could affect cardiac morphogenesis. To investigate whether offspring of women with selected HHD have an excess risk of CCM, the authors examined data from a nationwide birth defects monitoring program (BDMP) covering about 2.9 million births in the United States between 1982 and 1988. The system ascertains major birth defects diagnosed in the newborn period. An anonymous linkage procedure linked maternal obstetric records with newborn records using demographic, diagnostic, and geographic variables. A total of 1,239 mothers were identified with selected HHD (47 hereditary spherocytosis, 575 thalassemias, 310 sickle cell anemia, 88 other hereditary hemolytic anemias, 159 von Willebrand disease, and 60 other congenital coagulapathies). In all, 14 infants received a newborn discharge diagnosis of CCM (expected number based on population rates of CCM from the same hospitals and time period is 7.74; P = 0.0268). No single CCM entity accounted for this excess. In contrast, 8 infants had major non‐CCM defects (expected number 7.46; P = 0.466). These data suggest an excess risk of CCM among offspring of women with selected HHD. Further studies are needed to explore these findings and to evaluate the pathogenetic significance of this association.
Using multidimensional scaling on data from pairs of relatives to explore the dimensionality of categorical multifactorial traits
Authors: Meyer J. M. , Heath A. C. , Eaves L. J. , Chakravarti A.
Published: June 2005

An accurate specification of the dimensionality and ordering of categorical multifactorial phenotypes (e.g., smoking status, including heavy, moderate, light, and nonsmokers) is an important prerequisite for the genetic analysis of these traits. Typically, phenotypic dimensionality and ordering are determined by comparing the relative fits of alternative parametric threshold models. Here, a method of analysis is described which addresses the same issue of trait dimensionality but does not require parametric assumptions. Specifically, we detail how nonmetric multidimensional scaling (MDS), applied to contingency tables which cross‐classify the phenotypes or responses of one relative with another, may be used to explore trait dimensionality. Scaling results from deterministic simulation studies indicate that the latent structure of categorical phenotypes can be recovered with nonmetric MDS. Results from stochastic simulations, however, indicate that the accuracy of recovery, as well as the rejection of models of incorrect dimensionality, are strongly dependent upon sample size and the latent liability correlation between relatives. As an application of the method, the dimensionality of a measure of smoking status in 1,656 pairs of monozygotic twins ascertained through the American Association of Retired Persons is considered. The MDS results indicate that the onset of the smoking habit and the quantity smoked in this aging population represent a unidimensional process. The implication this finding has for subsequent genetic analysis is discussed. © 1992 Wiley‐Liss, Inc.
Specificity and sensitivity of hexosaminidase assays and DNA analysis for the detection of tay‐sachs disease gene carriers among Ashkenazic Jews
Authors: Fernandes Maria J. G. , Kaplan Feige , Clow Caroline L. , Hechtman Peter , Scriver Charles R. , Mulvihill John. J.
Published: June 2005

Tay‐Sachs disease (TSD), a neurodegenerative disorder resulting from a deficiency of the lysosomal enzyme hexosaminidase A (HexA), clusters in Ashkenazic Jews. Population‐based screening programs to detect carriers of TSD genes by means of HexA assays have been active since the 1970s. The recent characterization of 3 mutations in the HEXA gene (in exon 7, exon 11, and intron 12), which account for over 90% of HEXA mutations in Ashkenazim, appeared to offer better options for screening and diagnosis. The relative frequencies of the three mutations in Montreal are similar to those reported in four other North American populations. We compared enzyme and DNA analyses to determine specificity and sensitivity of each test when the other was used as the confirmatory procedure. Neither procedure has a sensitivity of 1.0. Maximum sensitivity and specificity were achieved by using both tests together. The findings here are likely to apply to most cases where the variant screened enzyme phenotype can result from more than one mutation. © 1992 Wiley‐Liss, Inc.
Genetic analysis of drinking behavior in World War II veteran twins
Authors: Carmelli Dorit , Heath Andrew C. , Robinette Dennis
Published: June 2005

The objective of the present study was to investigate longitudinal changes in drinking behaviors of adult male twins and model these changes as a function of genetic and environmental influences. Alcohol data available for World War II veteran twins, first surveyed in 1967–69 and followed up during 1983–85, were used to examine components of variability in measures of alcohol consumption. Multivariate biometric analyses of these data indicated 1) longitudinal stability of drinking behaviors in this cohort, 2) a significant contribution of genetic factors to the observed stability that accounted for more than 80% of the stable variation in frequency and in quantity of alcohol consumed per drinking occasion, and 3) evidence for a significant contribution of shared environmental influences to drinking of specific beverages (e.g., wine). The implications of these results for issues of health in the elderly are considered. © 1993 Wiley‐Liss, Inc.
Labman and Linkman: A data management system specifically designed for genome searches of complex diseases
Authors: Adams Phillip
Published: June 2005

Two programs have been developed to manage linkage analysis data. The first program, LABMAN, is a comprehensive laboratory data management system organizing pedigrees, blood DNA samples, DNA markers, Southern blot or polyacrylamide gels, autoradiographs, and marker‐allele typings generated from these samples. Output includes mendelization checks for genetic incompatibilities in typings and formatted files ready for linkage analysis. LABMAN can also compress highly polymorphic allele systems into smaller allele systems facilitating analysis of large systems. The second program, LINKMAN, provides data management for lod score output from linkage analyses. It reads linkage analysis output files, calculates lod scores by family, associates lod scores with specific marker and family identifiers, and stores these data in a database where they can be combined with lod scores from previous analyses. LINKMAN easily incorporates any of a wide variety of genetic models. It produces formatted output of lod scores by user‐specified criteria for reports or as ASCII files for input to other programs. If desired, tests of homogeneity of linkage across families can be run via the HOMOG program [Ott, 1991] and their output included in reports.

The programs include features critical for conducting genome searches of complex diseases: They are easy‐to‐use, well‐tested, and reliable. Data from multi‐center investigations can be easily combined for analysis. Moreover, they include extensive error‐checking capabilities, and they are specifically set up to protect blindness between laboratory workers and data analysts. LABMAN and LINKMAN are currently available free of charge under DOS. © 1994 Wiley‐Liss, Inc.
Segregation analyses of four urinary caffeine metabolite ratios implicated in the determination of human acetylation phenotypes
Authors: Vincent‐Viry Monique , da Silva Pontes Zelia Braz Vieira , Gueguen René , Galteau Marie‐Madeleine , Siest Gérard
Published: June 2005

Human acetylation phenotypes were determined with caffeine (137X) as the test substance, improved by measuring urinary caffeine metabolites with a previously described HPLC method. Caffeine, 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU), 1‐methylxanthine (1X), 1‐methyluric acid (IU), 1,7‐dimethylxanthine (17X), and 1,7‐dimethyluric acid (17U) were quantified. This study tested the hypothesis, suggested by previous studies, that the acetylation polymorphism is strongly influenced by a major gene. Phenotypes were assessed by using four urinary caffeine metabolite ratios: AFMU/1X, AFMU/[1X + 1U + 17U], AFMU/[AFMU + 1X + 1U], and AFMU/[1X + 1U + 17X + 17U] in a population included 281 nuclear family members who were healthy volunteer subjects. Each urinary ratio revealed strong familial aggregation with correlations between parents and offspring varying from 0.340 to 0.486 as a function of the ratio considered, and between sibs from 0.410 to 0.512 whereas correlations among spouses were not significant, excluding an effect of environmental factors. Segregation analyses were conducted upon these four ratios testing a series of specific models of inheritance and gave evidence for single locus control of N‐acetyltransferase (NAT) activity, with Mendelian codominant transmission using the AFMU/1X, AFMU/[1X + 1U + 17U], and AFMU/[1X + 1U + 17X + 17U] ratios. The slow allelic frequencies were 0.739, 0.753, and 0.724, respectively, and the phenotypic concordance was 90 to 92% with the AFMU/1X ratio. The familial aggregation observed in using the AFMU/[AFMU + 1X + 1U] ratio was consistent with a recessive transmission for the allele controlling the homozygous slow phenotype. This last ratio is not convenient to differentiate rapid heterozygous and homozygous phenotype. Considering the number of misclassified subjects, this study would be completed by genotyping the same families as demonstrated by some authors who predicted 97.5% of acetylation phenotype when using PCR‐based DNA amplification test. © 1994 Wiley‐Liss, Inc.
Recurrence risk for major congenital heart defects in Sweden: A registry study
Authors: Pradat Pierre
Published: June 2005

During the period 1981–1986, 1605 infants presenting a major congenital heart defect (CHD) were identified in Sweden. Using the personal identification numbers of the mothers, 1507 of them could be linked to the Medical Birth Registry and two controls were selected for each infant. For this total of 4521 infants, 2686 postoccurrence sibs born during the period 1981–1989 were identified from the Medical Birth Registry. The tendency to have one or more sibs was higher among cases than among controls and was correlated to the life status of the proband. This tendency did not vary according to the type of CHD when controlling for life status. The prevalence at birth of CHD was almost four times higher among sibs of CHD infants than among sibs of normal infants. The tendency to have a sib with an extracardiac malformation did not differ between CHD probands and normal probands. The importance of only including births occurring after the proband when evaluating recurrence risks is stressed. © 1994 Wiley‐Liss, Inc.
Comparative epidemiology of selected midline congenital abnormalities
Authors: Yang Ping , Khoury Muin J. , Stewart Walter F. , Beaty Terri H. , Chee Elsbeth , Beatty Jennifer C. , Diamond Earl L. , Gordis Leon
Published: June 2005

We present comparative epidemiologic characteristics of five congenital abnormalities that have been suggested to result from midline abnormal developmental disturbances: esophageal atresia with or without tracheoesophageal fistula (EA/TEF), imperforate anus with or without fistula (IA/F), omphalocele (OM), bladder exstrophy (BE), and diaphragmatic hernia (DH). The purpose was to assess the extent of epidemiologic similarities among these five defects. Data were collected as part of a population‐based case‐control study of infants with these defects born to mothers residing in Maryland, Washington, D.C., or Northern Virginia from 1980 through 1987. The estimated annual birth prevalences (per 10,000 live births) and 95% confidence intervals (CI) of these five defects were 0.40 (0.26–0.61) for BE, 1.34 (1.08–1.67) for OM, 1.59 (1.29–1.95) for DH, 2.11 (1.76–2.53) for EA/TEF, and 2.97 (2.55–3.46) for IA/F. The birth prevalence of IA/F and DH increased between 1980 and 1987. In contrast to the other four defects, DH showed a significant male preponderance (rate ratio 1.57, 95% CI 1.03–2.47), a significant white excess (rate ratio white:other, 1.56, 95% CI 1.00–2.48), and a lower proportion of multiple associated defects (30% vs. 46–61%). We concluded from this study that the descriptive epidemiology of diaphragmatic hernia is different from that of the other four defects. This finding may imply differences in etiologic and pathogenetic mechanisms underlying DH. © 1994 Wiley‐Liss, Inc.
Guanidine to adenine (G/A) substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI levels in chinese non‐smokers
Authors: Saha N. , Tay J. S. H. , Low P. S. , Humphries S. E.
Published: June 2005

The influence of the guanidine to adenine (G/A) substitution in the promoter region of the apolipoprotein (apo) AI gene (at −75 bp) on serum lipids and apolipoproteins was studied in 287 healthy Chinese of both sexes in Singapore. Women had significantly higher levels of high‐density lipoprotein cholesterol (HDLC) and apo AI and lower low‐density lipoprotein cholesterol (LDLC). The distribution of genotypes was at Hardy‐Weinberg equilibrium. The frequency of the A allele in the Chinese was significantly higher [0.27; 95% confidence interval (CI) 0.24–0.31] than that reported in Caucasians (0.12; 95% CI 0.09–0.14). In men, the A allele was associated with 20% higher apo AI; this association was completely absent in women. Furthermore, in men this association was only observed in those who had never smoked, and was absent in smokers. The G/A substitution explained 9% (P < 0.02) of the sample variance of apo AI in non‐smoking men. The modulating influence of smoking could not be examined in women because too few women smoke. Although the impact of this polymorphism is modulated by hormones and smoking, it is of importance in determining levels of apo AI in healthy Chinese individuals. No association of the G/A substitution of the apo AI gene was observed with any other lipid traits. © 1994 Wiley‐Liss, Inc.
Genetic influences on age‐related change in total cholesterol, low density lipoprotein‐cholesterol and triglyceride levels: Longitudinal apolipoprotein E genotype effects
Authors: Jarvik Gail Pairitz , Austin Melissa A. , Fabsitz Richard R. , Auwerx Johan , Reed Terry , Christian Joe C. , Deeb Samir
Published: June 2005

This study addressed the possible influence of apolipoprotein E (apo E) genotype on age‐related changes in total cholesterol (TC), low density lipoprotein‐cholesterol (LDL‐C), and triglyceride (TG) levels in older males. Apo E is a component of LDL, is a ligand for the LDL receptor, and apo E genotype has been consistently associated with variation in mean levels of TC and LDL‐C, and also appears to influence TG levels. Using male twins followed longitudinally between mean ages of 48 and 63 years, the change in TC, LDL‐C, and TG over time for individuals with the ϵ3ϵ3 and the ϵ3ϵ4 genotypes was contrasted. At exam 1 mean TC and LDL‐C levels were lower in the ϵ3ϵ3 group than in the ϵ3ϵ4 group, but at exam 3 mean TC and LDL‐C levels were significantly higher in the ϵ3ϵ3 group than in the ϵ3ϵ4 group. The rate of change in TC and LDL‐C with age differed significantly between ϵ3ϵ3 and ϵ3ϵ4 groups. Results for TG were not statistically significantly. These findings suggest that the apo E genotype effects on risk of coronary artery disease may be age‐dependent. This study demonstrates the value of longitudinal studies in refining models for genetic risk factors for disease. © 1994 Wiley‐Liss, Inc.
Familial aggregation of cardiovascular diseases in African‐American pedigrees
Authors: Rotimi Charles , Cooper Richard , Cao Guichan , Sundarum Callie , McGee Daniel
Published: June 2005

Familial aggregation of cardiovascular diseases and diabetes has been consistently demonstrated. However, virtually all of the evidence on the familial patterns of these diseases has come from white population samples. This study evaluates the level of familial excess risk among first degree relatives of 232 African‐American pedigrees which included 1,420 individuals recruited from the Chicago, IL, area. Excess disease risk was observed among relatives (parents and offsprings) of affected probands compared to relatives of unaffected probands for coronary heart disease (odds ratio [OR] = 5.30; 95% confidence interval [CI] = 2.51–11.23); hypertension (OR = 1.98; CI = 1.41–2.80); stroke (OR = 3.24; CI = 1.08–9.70); and diabetes (OR = 2.95; CI = 1.55–5.62). The results of this study clearly show that coronary heart disease, hypertension, stroke, and diabetes aggregate in some African‐American families and not others. Unaffected relatives of persons suffering from these diseases should be encouraged to have their blood pressure, lipid, and blood glucose levels measured at frequent intervals. These recommendations are particularly urgent in African‐American communities because of the disproportionately high morbidity and mortality experienced from cardiovascular diseases and diabetes. © 1994 Wiley‐Liss, Inc.
Inferring the direction of causation in cross‐sectional twin data: Theoretical and empirical considerations
Authors: Duffy David L. , Martin Nicholas G.
Published: June 2005

A recent multivariate extension of the classical twin study in theory allows the inference of the direction of causation between correlated traits solely using cross‐sectional data. In this paper we briefly review this model and assess its usefulness by applying it to a number of pairs of biological and psychological variables between which the nature of the causative relationship is already known. We conclude that the method has a number of biases and limitations. If a causative relationship at the phenotypic level exists between two traits, the correct direction of causation is usually identifiable, providing the reliability and validity of the measures are known. Failure to correctly specify a measurement model can lead to incorrect tests of hypotheses. Difficulties can also occur when discriminating between a direct causative relationship and a correlation due to common genetic or environmental determinants, but these occur in predictable situations. If these considerations are taken into account in interpretation of results, the true nature of the association between traits can often be correctly identified, or at least included in a subgroup of best fitting models. © 1994 Wiley‐Liss, Inc.
Epidemiology of retinitis pigmentosa in the valencian community (Spain)
Authors: Nájera C. , Millán J. M. , Beneyto M. , Prieto F.
Published: June 2005

The purposes of this study are to determine the frequencies of the different genetic forms of retinitis pigmentosa and to perform segregation analysis in the different genetic subtypes. Retinitis pigmentosa was diagnosed in 263 persons from 132 families. The frequency of the autosomal recessive type was the highest (31.8%) while the X‐linked type was very rare (1.5%). The frequency of autosomal dominant type was 14.4% and the simplex cases constituted half of the total cases of RP registered in our community. In conclusion, in our population the high proportion of simplex cases and the low number of X‐linked families are noticeable. The result of segregation analysis showed good agreement with expectation in autosomal dominant and autosomal recessive families but no more than 60% of all simplex cases were autosomal recessive. The proportion of sporadic cases was estimated statistically to be 39.9% of the total simplex cases. © Wiley‐Liss, Inc.
Apolipoprotein E4 allele and Alzheimer disease: Examination of Allelic association and effect on age at onset in both early‐and late‐onset cases
Authors: Locke P. A. , Conneally P. M. , Tanzi R. E. , Gusella J. F. , Haines J. L.
Published: June 2005

An increased frequency of the apolipoprotein E type 4 allele (APOE‐4) has previously been associated with both late‐onset sporadic and late‐onset familial Alzheimer disease (AD) [Strittmatter et al. (1993) Proc Natl Acad Sci USA 90:1977–1981; Saunders et al. (1993a) Neurology 43:1467–1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early‐ and late‐onset cases. An increased frequency of the APOE‐4 allele was found only among the late‐onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE‐4 homozygotes (in late onset families) compared to either APOE‐4 heterozygotes or individuals not carrying an APOE‐4 allele. We also observed a significantly decreased frequency of the APOE‐2 allele in both the early‐and late‐onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibility to AD. © Wiley‐Liss, Inc.
Statistical validity for testing associations between genetic markers and quantitative traits in family data
Authors: Nick Todd G. , George Varghese , Elston Robert C. , Wilson Alexander F.
Published: June 2005

In genetic analysis it is often of interest to analyze associations between traits of unknown genetic etiology and genetic markers from pedigree data. Statistical methods that assume independence of pedigree members cannot be used because they disregard the statistical dependencies of members in a pedigree. For quantitative traits, a regression model proposed by George and Elston [Genet Epidemiol 4:193–201, 1987] uses an asymptotic likelihood ratio test and incorporates a correlation structure that allows for statistical dependence among the pedigree members. The statistical validity of this test is assessed for finite samples by measuring the discrepancy between the empirical and theoretical chi‐square distributions. The variance of the mean of the dependent variable is determined to be related to this discrepancy and can be used to determine whether a pedigree structure is large enough for making valid statistical inferences on the basis of the asymptotic test. A multi‐generational pedigree of 200 or so individuals should in many cases be sufficient for valid results when using the asymptotic likelihood ratio test for the association between markers and continuous traits. © 1995 Wiley‐Liss, Inc.
Asymptotic distributions of polylocus test statistics
Authors: Goldstein Darlene R.
Published: June 2005

Polylocus linkage analysis methods are modified two‐point analyses which aim to approach the information gain of multilocus analysis. Terwilliger and Ott [(1992) Am J Hum Genet 51:A202, (1993) Genet Epidemiol 10:477–482] put forth two such methods. This paper presents asymptotic approximations to the null distribution of the likelihood ratio statistics for these two methods, correcting earlier reports [Terwilliger and Ott (1993) Genet Epidemiol 10:477–482; Schaid and Elston (1994) Genet Epidemiol 11:1–17]. The performance of the approximations is then assessed for finite samples of fully informative meioses. © 1995 Wiley‐Liss, Inc.
Statistical methodology for estimating twin similarity with respect to a dichotomous trait
Authors: Donner Allan , Klar Neil , Eliasziw Michael
Published: June 2005

Statistical methodology is presented for the estimation of twin similarity with respect to a dichotomous trait. The methodology focuses on the intraclass correlation as the parameter of interest and is analogous to methodology commonly applied to continuous outcome data. For inference problems involving a single sample, confidence interval construction and significance testing are discussed. For two sample problems, test procedures are provided that are an alternative to an approach recently presented by Ramakrishnan et al. [(1992) Genet Epidemiol 9:273–287 (1)]. Two examples based on published data sets are given to illustrate the proposed techniques. ©1995 Wiley‐Liss, Inc.
No association of apolipoprotein A‐IV codon 347 and 360 variation with atherosclerosis and lipid transport in a sample of mixed hyperlipidemics
Authors: Carrejo Maurita H. , Sharrett A. Richey , Patsch Wolfgang , Boerwinkle Eric
Published: June 2005

Genetic variation at the apolipoprotein (apo) A‐I/C‐III/A‐IV gene cluster on chromosome 11 has been associated with differences in occurrence of atherosclerosis and with variability in lipid levels among hypercholesterolemic‐hypertriglyceridemic individuals. The functional cause of the association is not known, but polymorphisms of the apo A‐IV gene are of interest because apo A‐IV is involved in both triglyceride and cholesterol metabolism. Two mutations in the apo A‐IV gene, 347T→S and 360Q→H, are known to cause amino acid substitutions in the mature protein. These polymorphisms were typed in a sample of 119 subjects with high cholesterol and high triglycerides in whom carotid artery wall thickness was previously shown to be strongly associated with silent polymorphic variation in the A‐I/C‐III/A‐IV gene cluster.

The relative allele frequencies were 0.83 and 0.17 for codon 347T→S, and 0.95 and 0.05 for codon 360Q→H. These polymorphisms did not show a statistically significant relationship with prevalent hypertension, diabetes, or cardiovascular disease or with plasma lipid levels. Most importantly, these amino acid substitutions in apo A‐IV were not associated with carotid artery wall thickness. Therefore, the genetic cause of disease variability in a sample of mixed hyperlipidemics is not amino acid substitutions in codons 347 or 360 of the apolipoprotein A‐IV gene. ©1995 Wiley‐Liss, Inc.
Variation in HLA‐associated risks of childhood insulin‐dependent diabetes in the finnish population: II. Haplotype effects
Authors: Thomas Duncan , Pitkäniemi Janne , Langholz Bryan , Tuomilehto‐Wolf Eva , Tuomilehto Jaakko ,   DiMe Study Group
Published: June 2005

We fitted models for the main effects of alleles at the HLA‐A, B, and DR loci and their haplotypes on the risk of insulin‐dependent diabetes mellitus (IDDM). Empirical Bayes methods were used, assuming independent exchangeable normal priors for effects at each locus separately and for haplotype effects. A pure main effects model, pure haplotype effects model, and a combined model were fitted using Gibbs sampling. The main effects model showed that the DR locus had the largest variation in risk between alleles, followed by the B locus; significance tests for each allele in this model were in general agreement with those in the companion paper [Langholz et al. (1995) Genet Epidemiol 12:441–453], although all relative risks were shrunk toward 1.0 in the empirical Bayes analysis. The variance estimate for pure haplotype effects was substantially larger than for any of the three main effects considered in this analysis, but in the combined model, the DR locus showed larger variability than the haplotype deviations. We confirmed that haplotype A2/B56/DR4 previously reported to be common in Finnish diabetics does indeed confer unusually high risk (relative risk = 7.6, P < 0.001), but found this to be only 1.9 times higher than predicted by its component main effects (P = 0.046). All of the other haplotypes could be adequately explained by their main effects. Empirical Bayes methods provide a natural means of dealing with the problems of multiple comparisons, multicolinearity, and sparse data that complicate the analysis of HLA data. ©1995 Wiley‐Liss, Inc.
Association of childhood rhabdomyosarcoma with neurofibromatosis type i and birth defects
Authors: Yang P. , Grufferman S. , Khoury M. J. , Schwartz A. G. , Kowalski J. , Ruymann F. B. , Maurer H. M.
Published: June 2005

Rhabdomyosarcoma (RMS) is an uncommon malignant soft tissue sarcoma whose cause is largely unknown. Reported risk factors include genetic alterations (e.g., p53 mutations, a defective gene at 11p15.5, or specific chromosomal translocation of t(2:13)), and parents' use of drugs around the time of conception. We present results from a national, case‐control study of 249 RMS cases (170 males and 79 females) and 302 controls (196 males and 106 females). The cases, aged 0–20 years at diagnosis, were identified via the Intergroup RMS Study‐III during 1982–1988. Controls were selected by random digit telephone dialing. As a supplement to the original study, information on genetic diseases and birth defects (BD) was collected from the subjects' parents by telephone interview. Fifty‐six (22.5%) cases and 55 (18.2%) controls were reported to have genetic diseases or BD (odds ratio [OR] = 1.30,95% confidence interval [CI] = 0.85–2.02, P = .21). The case group had a significantly higher frequency of neurofibromatosis type I (NF1) than did the control group, i.e., five cases (2.0%) had NF1 vs. zero controls (P = .02). The case group also had a higher frequency of major BDs than did the control group (6.0% vs. 2.6%, OR = 2.36, 95% CI = 0.92–6.52, P = .05). However, this excess was only observed in males (7.6% vs. 2.6%, OR = 3.16, 95% CI = 1.02–10.41, P = .02). Among the 15 cases having both RMS and major BDs, six (40.0%) had both conditions in the same regional anatomic site: Two (13.3%) had both in the extremities, two (13.3%) in the genitourinary system, and two in the head and neck. These findings suggest that common genetic mechanisms or in utero exposures may be invilved in the development of many childhood tumors and congenital abnormalities. ©1995 Wiley‐Liss, Inc.
Model‐free association analysis of a rare Disease
Authors: Bailey‐Wilson Joan E. , Sorant Benjamin , Sorant Alexa J. , Paul Christel M. , Elston Robert C.
Published: June 2005

Model‐free methods of testing for association of a disease with alleles at a marker locus were used to analyze simulated data for a rare disease locus and 360 marker loci distributed at 2 cM intervals along six chromosomes. After adjustment for multiple tests, there was no evidence of significant heterogeneity of parental allele frequencies between a sample of parents with at least one affected child and a sample of parents with no affected children. Several significant deviations from Hardy‐Weinberg equilibrium were detected after Bonferroni correction but these were Type I errors. After adjusting for multiple tests, the model‐free test for association detected significant associations of alleles at two loci with the disease. These associations were in fact part of the generating model for the simulated data. However, these methods were unable to detect two other major loci contributing to the disease since these loci were not associated with any of the marker loci. ©1995 Wiley‐Liss, Inc.
Identification of susceptibility loci contributing to a complex disease using conventional segregation, linkage, and association methods
Authors: Falk C. T. , Ashley A. , Lamb N. , Sherman S. L.
Published: June 2005

We set out to apply conventional analytic methods to a GAW data set of nuclear families with an oligogenic disease that has a population prevalence of 0.023. We chose methods generally applied to disorders with at least one major gene. Our approaches included: (1) complex segregation analysis under two models of ascertainment, (2) linkage analysis assuming either a single‐locus trait with possible genetic heterogeneity or a two‐locus trait, and (3) allelic association studies using both a case/control approach and the haplotype relative risk (HRR) test. The association study was the only analysis of the three that provided evidence for genes playing a role in the etiology of this disorder. ©1995 Wiley‐Liss, Inc.
Effects of marker information on sib‐pair linkage analysis of a rare disease
Authors: Korczak Jeannette F. , Pugh Elizabeth W. , Premkumar Smita , Guo Xiuqing , Elston Robert C. , Bailey‐Wilson Joan E.
Published: June 2005

Model‐free sib‐pair linkage analysis was used to screen the GAW9 ‐ Problem 1 data set for evidence of linkage of a rare disease to any of 360 highly polymorphic marker loci. Negative regressions nominally significant at the α = 0.05 level were obtained for 44 markers; however all of these proved to be Type I errors. None of the four disease loci were detected by sib‐pair linkage, which was not surprising, given the particular model and sampling scheme used to generate these data. Neither deleting parental marker genotypic information nor misspecifying marker allele frequency estimates substantially increased the Type I error rate. A two‐stage testing procedure using a 10 or 20 cM map and a liberal first stage significance level gave the same overall results as a one‐stage 2 cM map but required only about 42% or 22% as many markers, respectively. ©1995 Wiley‐Liss, Inc.