Analysis of marker segregation in the large Alzheimer pedigree, FAD4, leads to the conclusion, with a type I error of 5%, of linkage heterogeneity between two branches of the pedigree: the disease ...cosegregates with chromosome 21 markers flanking the APP area in one branch and not in the other one. Thus, we conclude that a single mutation in the chromosome 21 region surrounding APP cannot be responsible for all the affected cases in this pedigree.
The MASC method has been applied to the GAW5 data. The method uses the simultaneous information on association and segregation of the HLA marker with the disease and the segregation of the HLA marker ...in affected families. It also takes into account the differential risk for parents of a patient, as well as the different HLA haplotype sharing, according to the HLA genotype of the patient. The goodness of fit of several genetic models has been tested. The observed data are not compatible with a two-allele, one-locus model, but they fit a three-allele, one-locus model and a complementation two-locus model if additional familial correlation is allowed.
For elucidating the genetic component of multifactorial diseases, it is important to investigate the effect of several factors and the possible interaction between them. In particular, for many ...diseases it is interesting to study the interactive effect of two genes. In this context, the marker-association-segregation chi 2 method (MASC), initially proposed to detect the involvement of a candidate gene in multifactorial diseases, is developed here to investigate the involvement of two candidate genes and to model the joint effect of these two genes. In particular, it is possible to precisely determine whether the joint effect of both genes is multiplicative. This extension simultaneously uses information on two markers, one for each candidate gene, at both the population and the familial segregation level. We show here that there can be an important gai of power to detect the effect of a second gene in a disease when information is used simultaneously on two markers instead of studying each marker separately. This extension of MASC is then applied on a sample of insulin-dependent diabetes (IDD) families typed for the markers of two candidate regions: HLA and that of the insulin gene (INS). This analysis allows us to confirm the involvement of INS in IDD, and the best-fitting model is a multiplicative (noninteractive) effect of HLA and INS, with a biallelic locus for INS and a complementation model for HLA.
Antiphospholipid antibodies (aPL) are noted with increased frequency in patients with systemic lupus erythematosus (SLE). The main manifestations found to be associated with aPL are arterial and ...venous thrombotic events, thrombocytopenia, and recurrent pregnancy loss. This study is an attempt to define the incidence of aPL in patients with childhood-onset SLE and in their relatives and to correlate their presence with clinical manifestations, and especially, to evaluate the risk of thrombosis in aPL-positive subjects.
We studied 37 unrelated patients and 107 of their first-degree relatives. VDRL, IgG and IgM anticardiolipin, and IgG antiphosphatidylethanolamine antibodies were studied in all probands during periods of clinical remission and in first-degree relatives at the time of interview. Lupus anticoagulant had only been studied in probands during an SLE flare-up.
Thirty-eight percent of probands and 19% of relatives were positive for at least one aPL, with little overlap between the different aPL studied. -No aPL-negative proband developed thrombosis. Two of the aPL-positive probands had thrombotic events before testing, and a third one showed thrombosis after testing. Only two probands had high levels of IgG aCL and showed thrombosis. The occurrence of aPL positivity in relatives was not always related to its presence in probands. None of the aPL-positive relatives had had thrombosis, but recurrent fetal loss was noted in one aPL-positive mother with SLE. Although there was a high frequency of SLE, SLE-like disease, auto-immune disorders or positive serological findings for lupus in first-degree relatives, many of these relatives did not test positive for aPL.
The high levels of IgG aCL may be considered a risk factor for thrombosis. Findings in relatives suggest a multifactorial origin for autoimmune disease and antibody production.
The objective of this study is to evaluate the efficacy of a model-free linkage statistics for finding evidence of linkage using two different maps and to illustrate how the comparison of results ...from several populations might provide insight into the underlying genetic etiology of the disease of interest. The results obtained in terms of detection of the risk loci and threshold for declaring linkage and power are very similar for a dense SNP map and a sparser microsatellite map. The populations differed in terms of family ascertainment and diagnosis criteria, leading to different power to detect the individual underlying disease loci. Our results for the individual replicates are consistent with the disease model used in the simulation.
Clinical heterogeneity of a disease may reflect an underlying genetic heterogeneity, which may hinder the detection of trait loci. Consequently, many statistical methods have been developed that ...allow for the detection of linkage and/or association signals in the presence of heterogeneity.This report describes the work of two parallel investigations into similar approaches to ordered subset analysis, based on an observed covariate, in the framework of family-based association analysis using Genetic Analysis Workshop 15 simulated data.With an appropriate choice of covariate, both approaches allow detection of two loci that are undetectable by the classical transmission-disequilibrium test. For a third locus, detectable by the classical transmission-disequilibrium test, a substantial increase of power of detection is shown.
Although the retinoblastoma gene has been isolated and sequenced, the difference in penetrance and expressivity among families has not yet been fully explained. Balanced chromosomal insertion ...involving the 13q14 regions has been shown to account for some families with several unaffected carriers. Since there could be cases with karyotypically undetectable insertions, we tested whether this mechanism was general enough to explain the whole difference in expressivity among families. Using 166 pedigrees, reported in nine series available in the literature (including our own), we conclude that balanced insertion cannot entirely explain the familial data, even if we allow for a reduced viability of unbalanced gametes. Other mechanisms are proposed and discussed in this paper.
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