摘要:

AbstractIn this study we compared parameter estimates and model hypotheses in pedigree data collected by fixed sampling with estimates and hypotheses derived by sequential sampling. Employing a fixed sampling scheme, we previously analyzed data on relatives of 159 childhood sarcoma patients. We have now extracted from that data set individuals who would have been included in a sequentially sampled study. We applied segregation analysis to the truncated data, to determine the mode of inheritance and major locus parameter estimates. With data from both sampling schemes we made a family‐by‐family comparison to determine each family's contribution to a major gene model. The two sampling schemes yielded similar results: we detected segregation of a dominant major gene and obtained similar major locus parameter estimates. However, the sequential sampling scheme derived these conclusions from data on 982 relatives rather than the 2,451 ascertained in the fixed sampling scheme. The sequential sampling scheme failed to identify only one of the kindreds likely to be segregating the gene. For this data set, the sequential sampling scheme would have provided an efficient mechanism to discriminate genetic hypotheses and would have permitted focus of resources on the specific kindreds likely to segregate a major gene. © 1992 Wiley‐Lis

ISSN:0741-0395    

DOI:10.1002/gepi.1370090502

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractHuman apolipoprotein A‐IV (APO A‐IV) exhibits a common protein polymorphism detectable by isoelectric focusing (IEF) due to a single base substitution at codon 360 which replaces the frequently occurring glutamine residue (allele 1) with histidine (allele 2). Recently, sequence analysis of the APO A‐IV coding region has revealed another common nucleotide substitution at codon 347 which converts the commonly present threonine residue (allele A) into serine (allele T). In order to investigate the extent of genetic variation at codon 347, we screened DNA samples from 192 unrelated individuals using a polymerase chain reaction based assay. The frequencies of the two alleles,A‐IV*AandA‐IV*T, were 0.81 and 0.19, respectively, with average heterozygosity 0.31. Genetic screening of the corresponding 192 plasma samples by IEF gave frequencies of 0.922 and 0.078 for theA‐IV*1andA‐IV*2alleles, respectively, at codon 360 with average heterozygosity 0.14. Genotype data at the two polymorphic sites were used to assign unequivocal haplotypes to all the 384 chromosomes. Of the expected four haplotypes (A1, T1, A2, and T2) only three were observed and their frequencies were 0.732 for A1, 0.190 for T1 and 0.078 for A2, with average heterozygosity 0.42. Although our data indicate significant linkage disequilibrium between the two sites (χ 12= 7.65,P>0.006, standardized disequilibrium constant ψ = −0.14) the degree of nonrandom association varied between alleles at the two sites. Based upon allele frequency data and variable linkage disequilibrium between alleles, we propose that the A2 and T1 haplotypes may have evolved from the parental A1 haplotype by two independent mutations. ©

ISSN:0741-0395    

DOI:10.1002/gepi.1370090503

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractTo gain insight into the variable expression of lung disease in α1‐antitrypsin (α1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25–75), total serum α1AT, oxidized serum α1AT, and total serum immunoglobulin E (IgE) were measured in α1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total α1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25–75, and oxidized α1AT are moderately influenced by Pi type. The effect of genotype‐by‐environment interaction between Pi type and pack‐years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi × pack‐years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi × age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi × pack‐years interaction effect on FEV1which Pi Z subjects ascertained for other reasons demonstrate. The effect of the Pi × pack‐years interaction on FEV1was no longer significant on a transformed scale, (FEV12,) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi × packs‐years interaction effect on FEF25–75to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype‐by‐environment interaction analyses into the study of the variable expression of lung disease in Pi

ISSN:0741-0395    

DOI:10.1002/gepi.1370090504

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractDementia of the Alzheimer type (DAT) is a neurodegenerative disorder which afflicts approximately 3% of the population. Genetic influences are indicated from twin and family studies although genetic heterogeneity has been suggested from both pedigree analyses and linkage investigations. Autosomal dominant inheritance with age‐dependent penetrance has been suggested in at least some families with DAT. In the present investigation, we examine memory and nonmemory task performance in 106 asymptomatic offspring (mean age 40.6 years) of 54 DAT probands. Intraclass sibling correlations revealed little evidence of sibling similarity for performance on three memory tasks which have been reported to be relatively sensitive to the memory losses accompanying DAT. Subsequent investigations of the distributions of the cognitive task scores in the offspring revealed evidence for a commingling of two distributions for the three memory tasks but not for the nonmemory measures. These findings are consistent with a hypothesis that these distributions reflect genotypic subgroups, carriers, and noncarriers, of a presumed DAT gene. © 1992 Wiley‐Liss,

ISSN:0741-0395    

DOI:10.1002/gepi.1370090505

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractMost complex diseases have not been amenable to genetic analysis under the assumption of single locus or multifactorial models. Consequently, interest has turned to the consideration of the properties of oligogenic models. i.e., genetic models involving a small number of genes. Nine two‐locus models of disease, representing both epistatic and heterogeneous genetic models, are investigated: three models of heterogeneity and six models of epistatis. For each model we derive formulas for the recurrence risk to various classes of relatives in terms of penetrances and gene frequencies. We also develop formulas for the components of variance for the epistatic models in terms of the same genetic parameters. The range of penetrances and the associated gene frequencies that predict a predetermined value for the population prevalence and recurrence risk to the sibling of proband are calculated for various rates of the prevalence and risk to sibs. It is found that for many of these genetic models, there is a very limited range of penetrances that fit a particular set of assumed risks. Estimated population prevalence and risks to sibs and monozygotic twins for bipolar and schizophrenia illness are used to test for compatibility with expected values for recurrence risks under these models. © 1992 Wiley‐Liss,

ISSN:0741-0395    

DOI:10.1002/gepi.1370090506

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractA method is presented for the preliminary ordering of loci on a chromosome using pairwise linkage data. The method is based on the biologically reasonable assumption that the ‘true’ order of a set of linked loci will be the one that minimizes the total length of the chromosome segment. Here the ‘length’ is defined as the sum of adjacent recombination fractions. The method searches for the optimal order, represented by a minimum distance map (MDMAP), even when it is not possible to examine then!/2 possible distinct orders for n loci. A computerized approach, using the simulated annealing algorithm of Kirkpatrick et al. [1983], forms the basis of the method. It can be applied to data from radiation hybrid experiments as well as that from conventional family linkage studies. The technique is applied to several sets of published data to illustrate how it performs in practice. The advantages and the disadvantages of the method are discussed so that it will be clear under what conditions it is likely to work well. When data sets are ‘complete,’ in the sense that all possible pairwise recombination fractions have estimates, and when no large clusters of extremely tightly linked loci are present, the method produces ordered sets of loci that agree well with those generated by other, more complex methods. Any discrepancies that occur are likely to be with respect to the orientation of nearest‐neighbor loci, where relative order cannot be reliably established by any method. The method thus provides a simple, rapid means of obtaining a preliminary order for a set of loci known to be in the same linkage group. © 1992 W

ISSN:0741-0395    

DOI:10.1002/gepi.1370090507

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0741-0395    

DOI:10.1002/gepi.1370090508

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0741-0395    

DOI:10.1002/gepi.1370090501

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY