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PubMed2003

Robustness of inference on measured covariates to misspecification of genetic random effects in family studies.

Family studies to identify disease-related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933-948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan.

Analysis of Variance↗
PubMed2003

Diagnostic tools in linkage analysis for quantitative traits.

Diagnostic methods are key components in any good statistical analysis. Because of the similarities between the variance components approach and regression analysis with respect to the normality assumption, when performing quantitative genetic linkage analysis using variance component methods, one must check the normality assumption of the quantitative trait and outliers. Thus, the main purposes of this paper are to describe methods for testing the normality assumption, to describe various diagnostic methods for identifying outliers, and to discuss the issues that may arise when outliers are present when using variance components models in quantitative trait linkage analysis. Data from the Rochester Family Heart Study are used to illustrate the various diagnostic methods and related issues.

Coronary Artery Disease↗
PubMed1999

A normalized identity-by-state statistic for linkage analysis of sib pairs.

A sib-pair analysis was performed on a simulated data set for a fictitious disease, with a prevalence of approximately 3% to 6%. The disease could manifest itself in a severe or mild form and the analyses focused primarily on families with the mild form, barring any misdiagnoses. The numbers of shared genes identical by descent (IBD) and identical by state (IBS) were used to detect linkage between the marker loci and the disease. The results of the two methods were compared. We considered the distribution of the number of shared alleles IBS (for different parental allele combinations) and suggest a normalized IBS method. A large proportion of pedigrees in this data set had at least one homozygous parent or both parents sharing a common gene, thus generating the need for an adjustment of the IBS method. Our results indicate that the normalized IBS method gives results similar to those obtained by the traditional IBD approach. The adjusted score requires no assumptions be made with regard to the allele frequencies.

Alleles↗
PubMed1999

Covariates in linkage analysis.

We apply a novel technique to detect significant covariates in linkage analysis using a logistic regression approach. An overall test of linkage is first performed to determine whether there is significant perturbation from the expected 50% sharing under the hypothesis of no linkage; if the overall test is significant, the importance of the individual covariate is assessed. In addition, association analyses were performed. These methods were applied to simulated data from multiple populations, and detected correct marker linkages and associations. No population heterogeneity was detected. These methods have the advantages of using all sib pairs and of providing a formal test for heterogeneity across populations.

Genetic Linkage↗
PubMed1999

An evaluation of affected-sib-pair methods and transmission/disequilibrium tests for detecting genes underlying a complex trait.

For the analysis of complex traits, it is of interest to compare a few nonparametric methods such as affected-sib-pair (ASP) analyses and transmission/disequilibrium tests (TDT). The affected-sib-pair approaches we have examined here are ASP and ALL-SP which are implemented in SIBPAIR program. We also applied the BETA program which has not so far been extensively compared with other methods. The study indicates that the ASP program and the BETA program give concordant results although BETA tends to give higher lod scores. However, when all sibs were included in the analysis (ALL-SP), linkage signals became weaker, compared with ASP and BETA. The TDT detected 66 positive signals at a significance level of 0.05 and identified a true locus. Overall, our results suggest that affected-sib-pair analysis has reasonable power (p < 0.0001) to detect linkage given the disease model and the family structure specified in the GAW11 Problem 2 data set.

Genetic Testing↗
PubMed1999

A generalized estimating equations approach to linkage analysis in sibships in relation to multiple markers and exposure factors.

We describe a multiple regression approach to nonparametric linkage analysis in sibships incorporating multiple genetic loci, environmental covariates, and interactions. The covariance in trait residuals between sib pairs is treated as the dependent variable, regressed upon identical-by-descent sharing probabilities and interaction effects, using generalized estimating equations to allow for the correlations among multiple sib pairs within a sibship. Individual covariates can also be introduced in the model for the trait means. An application to the GAW11 simulated data revealed linkage with each of the four simulated loci, as well as gene x environment interactions of E1 with loci C and D and gene x gene interactions among the cluster of loci A, B, and D.

Environment↗
PubMed1999

Stratification techniques to explore genotype environment interactions.

Linkage analysis was performed on the GAW11 Problem 2 data set using stratification to explore the effects of the environmental risk factors and the differences between mild and severe phenotypes. Analysis of the four study populations stratified by the two risk factors identified regions on chromosomes 3 and 5 with significant evidence for linkage. Other loci were sought by removing families consistent with linkage to the chromosome 3 locus. Our studies identified a locus on chromosome 3 (markers 43-46) associated with the mild phenotype in the presence of risk factor 1 and with the severe phenotype independent of risk factor 1. This suggests that distinct allelic variants at the chromosome 3 locus may cause different forms of disease. The locus identified on chromosome 5 (markers 36-39) was linked to the severe phenotype, but exposure to factor 1 or 2 may have a protective effect. The regions on chromosomes 3 and 5 appeared to have independent roles in disease etiology. Evidence for two loci on chromosome 1 linked to the mild form was found. The methods successfully identified linkages and interaction consistent with the generating model.

Environment↗
PubMed1999

A method for meta-analysis of genome searches: application to simulated data.

Genome searches have been performed for many complex traits, and in some cases several searches have been performed in a single disease. Replication of significant results is rare, and a systematic method of reviewing results from a number of searches is needed. A method for meta-analysis is presented which provides a systematic descriptive overview of the separate analyses while dealing with some of the problems specific to meta-analysis of genome searches. The results of two separate meta-analyses correctly indicate the presence of susceptibility loci on chromosomes 1, 3, and 5 in the GAW11 Problem 2 data.

Genetic Linkage↗
PubMed1999

Significant evidence for linkage of a simulated trait to D1G024--a conclusion reached using multiallelic transmission/disequilibrium tests.

We applied three versions of the transmission/disequilibrium test (TDT) for detecting linkage in nuclear families using the a priori information of possibly present association. For our analyses we employed all marker data for a simulated trait. Results for replicate 11 showed significant linkage to D1G024 using the multiallelic Tmhet statistic and the extended TDT. The TDT for the most frequent parental allele which had been applied successfully in previous studies failed to detect linkage. This result may have happened because the data did not arise from a realistic simulation of the evolution of a real population, where mutations might be expected to occur against a specific haplotype. Simulation studies are required to elucidate the applicability of the TDT for the most frequent parental allele in realistic situations. Furthermore, guidelines have to be developed for how to pool categories in large, sparse contingency tables to obtain larger cell frequencies and lower degrees of freedom.

Alleles↗
PubMed2001

Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment.

Recent studies have established that environmental factors can modify hippocampal structure and enhance function in adult rodents, but the extent to which genes and the environment exert differential contributions to hippocampal structural integrity in humans is unknown. Here, we applied the twin model in a large sample of elderly twin men to examine in late life the balance of environmental and genetic effects on the size of the hippocampus in comparison with other brain structures. This study provides novel evidence that the volume of the hippocampus, as measured on MRI, is subject to substantially less genetic control than are comparison brain regions also measured: temporal horn volume, midsagittal area of the corpus callosum, and intracranial volume (ICV). In particular, about 60% of the temporal horn variance and 80% of the callosal and ICV variance was attributable to genetic influences, whereas only 40% of the hippocampal variance was attributable to genetic influences. These results suggest that environment, whether by itself or in interaction with genes, has the potential of exerting greater and possibly longer control in modifying hippocampal size than other brain regions that are under greater genetic control. Considering the potential of environmental modification of this structure suggested by lower heritability, the hippocampus appears well-suited to support the dynamic processes of encoding and consolidation of new, declarataive memories.

Aged↗
PubMed2001

Statistical multilocus methods for disequilibrium analysis in complex traits.

Hundreds of thousands of SNP markers are being generated with the purpose of carrying out case-control association studies for complex traits, which are thought to be due to multiple underlying susceptibility genes. The number of markers is typically much larger than the number of observations so that joint analysis of marker genotypes and their interactions is not feasible. We discuss a two-stage approach to first select a small subset of markers and then model the effects of the selected markers on disease. Examples of two procedures for marker selection are given with subsequent modeling of main and interaction effects. The approaches are applied to a data set with 89 SNPs in lieu of a genome screen with many more markers.

Alleles↗
PubMed1995

Frequency and characteristics of familial aggregation of Paget's disease of bone.

The cause of Paget's disease of bone (PDB) is unknown. In an attempt to ascertain the proportion of familial cases and evaluate the influence of genetic factors on the occurrence of the disease, a study was undertaken based on 35 PDB patients from our Unit. Their families were investigated, with the participation of a total of 128 first-degree relatives. Fourteen (40%) of these 35 index cases had at least one other first-degree relative affected with PDB and were defined as "familial." The remaining 21 (60%) were considered "sporadic." The frequency of males in the familial cases (79%) was significantly higher than among the sporadics (29%; p < or = 0.01). Mean age at diagnosis (63.1 +/- 12.6 vs. 71.3 +/- 8.7; p < or = 0.02), proportion of polyostotic cases (85.7% vs. 52.4%, p < or = 0.05), and mean number of involved bones per patient (4.36 +/- 2.50 vs. 2.33 +/- 1.93, p < or = 0.01) differ significantly in the familial and sporadic groups. The disease appears to be transmitted via both paternal and maternal sides, and pedigree analysis suggested an autosomal dominant inheritance or multifactorial mechanism. Apart from green-and-blue eye color, which was clearly associated with familial grouping (OR 6.25, 95% CI 1.15-37.16, p < or = 0.01), crude analysis on several genetically based traits and environmental variables revealed no other significant differences between the groups. The adjusted odds ratio estimated for green-and-blue eye color was 2.92 (95% CI 0.38-22.74).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2025

Protective Effects of Genetic Proxies of Cognitive Reserve in Parkinson's Disease: A Longitudinal Multi-Cohort Study.

BACKGROUND: Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD. METHODS: Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage &#x2265;3, progression to a Montreal Cognitive Assessment score&#x2009;&#x2264;24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs. RESULTS: All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P&#x2009;<&#x2009;0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P&#x2009;=&#x2009;0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P&#x2009;=&#x2009;0.029). CONCLUSIONS: Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. &#xa9; 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Humans↗
PubMed2000

Multiplex PCR for detection of trait and virulence factors in enterohemorrhagic Escherichia coli serotypes.

A multiplex PCR assay was developed which allowed the simultaneous detection of five trait genes or virulence markers in enterohemorrhagic Escherichia coli (EHEC) serotypes. A primer pair, designed to detect a single base-pair mutation in the uidA gene, is specific only for the prototypic EHEC of O157:H7 serotype and its toxigenic, non-motile variants. In a similar way, primers to the eaeA gene of the gamma-intimin derivative specifically detects strains in the EHEC 1 clonal group, which consists mostly of O157:H7 and some O55:H7 serotypes. The other three primer pairs, specific for stx1, stx2 and both variants of ehxA genes, will detect the presence of these virulence genes in all EHEC serotypes. Analysis of 34 strains, including various serotypes of EHEC, Shiga toxin-producing E. coli and enteropathogenic E. coli, confirmed that the multiplex PCR assay detected the presence of these genes in a manner consistent with the known genotype of each respective strains.

Bacterial Proteins↗
PubMed2003

Novel approaches to identify low-penetrance cancer susceptibility genes using mouse models.

Studies of cancer predisposition have largely concentrated on the role of high-penetrance susceptibility genes. Less than 10% of the total human tumor burden, however, is accounted for by mutations in these genes. More genetic variation in cancer risk is likely to be due to commoner but lower penetrance alleles. In man, such modifier genes will be difficult to find since they do not segregate as single Mendelian traits. The mouse offers a powerful system for studying polygenic traits such as cancer and has been widely used for this purpose. Novel approaches that might accelerate the identification of these low-penetrance cancer susceptibility genes by using mouse models will be discussed.

Alleles↗
PubMed1983

Family study of congenital limb reduction abnormalities in Hungary 1975-1977.

A family study of 274 index patients with limb reduction malformations born in Hungary from 1975 to 1977 is reported. The majority of 789 first-degree relatives were personally examined. Information was collected on 1094 uncles and aunts and on 1095 cousins, and those affected by limb malformations were examined. Among 789 first-degree relatives six were affected by a similar malformation (radial, ulnar and central ray defects) and 1 by a malformation of a different type; no secondary cases of the same type were found among the relatives of patients with terminal transverse and amniogenic malformations, and with limb malformations which were part of syndromes or unclassifiable associations with other malformations. While a few rare types of limb defects are due to dominant genes, the aetiology of most cases is obscure. There is no evidence of sex-linked inheritance, of multifactorial causation or of environmental factors shared by relatives. These results are similar to those of an earlier study by Birch-Jensen.

Abnormalities, Multiple↗
PubMed2002

The power and statistical behaviour of allele-sharing statistics when applied to models with two disease loci.

We have evaluated the power for detecting a common trait determined by two loci, using seven statistics, of which five are implemented in the computer program SimWalk2, and two are implemented in GENEHUNTER. Unlike most previous reports which involve evaluations of the power of allele-sharing statistics for a single disease locus, we have used a simulated data set of general pedigrees in which a two-locus disease is segregating and evaluated several nonparametric linkage statistics implemented in the two programs. We found that the power for detecting linkage using the S(all) statistic in GENEHUNTER (GH, version 2.1), implemented as statistic E in SimWalk2 (version 2.82), is different in the two. The P values associated with statistic E output by SimWalk2 are consistently more conservative than those from GENEHUNTER except when the underlying model includes heterogeneity at a level of 50% where the P values output are very comparable. On the other hand, when the thresholds are determined empirically under the null hypothesis, S(all) in GENEHUNTER and statistic E have similar power.

Alleles↗