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F Clerget-Darpoux

Publications and source records attributed to F Clerget-Darpoux.

At least 19 recordsLinked to original sources
PubMed1992

Strategies based on marker information for the study of human diseases.

The goals and the ways of using genetic marker information when studying human disease are very different according to whether the disease or sub-entity of the disease is mendelian or if a 'disease gene' in the sense of a rare mutated allele does not exist but rather common genetic risk factors, each one normal if considered alone. In the former case, genetic markers are used in the aim of localizing the defective gene and a systematic screening of the genome seems to be an efficient strategy provided there is not too much ambiguity in the correspondence between phenotypes and genotypes. In the latter case, the goal is to find risk factors allowing us to predict better the risk for an individual and to define different risk groups resulting in greater power to show the potential role of other factors (genetic or environmental). In this situation, the use of the lod score method with random markers presents several disadvantages: first, the multiple testing problem is particularly crucial; second, false rejection of linkage may be induced by misspecification of the model describing the genetic basis of the disease; and last, the power of detecting linkage may be low. A strategy focusing on 'candidate gene' markers may be then more efficient.

Chromosome Mapping↗
PubMed1992

Proximal spinal muscular atrophy (SMA) types II and III in the same sibship are not caused by different alleles at the SMA locus on 5q.

Proximal spinal muscular atrophy (SMA) is a group of progressive muscular diseases recently mapped to chromosome 5q. SMA is usually classified into types I-III, and there are cases of two types of SMA in the same sibship. Becker and others later proposed that these sibships might be due to the existence of several alleles at the same locus predisposing to the different forms of the disease. In a sample of four sibships in which both SMA type II and SMA type III occur, this hypothesis was clearly rejected for the SMA locus on 5q, by using information on the segregation of linked markers (P less than .001). Thus the difference between SMA type II and SMA type III is not due to different alleles at the SMA locus on 5q. This finding is suggestive of an involvement of other factors, genetic or environmental, in the determination of disease severity in SMA.

Alleles↗
PubMed1992

Linkage of familial breast cancer to chromosome 17q21 may not be restricted to early-onset disease.

Lod scores for linkage between familial breast and ovarian cancer and markers on chromosome 17q21 are more frequently positive among families with disease diagnosed at younger ages than they are among older-onset families, suggesting that linkage is restricted to early-onset disease. However, for late-onset cases, the relative probability of sporadic rather than inherited disease is higher than previously suggested. If this correction is made, then later-onset families are much less informative; linkage heterogeneity based on age at onset is no longer significant; and for the sample of families as a whole, linkage is significant at a recombination fraction since demonstrated to be close to the correct local. There is probably more than one gene for inherited breast cancer, but heterogeneity may not be due to age at disease onset.

Adult↗
PubMed1991

A test based on the exact probability distribution of the chi 2 statistic--incorporation into the MASC method.

The MASC method (Clerget-Darpoux et al. 1988) to test genetic models in HLA associated disease makes use of a test of goodness-of-fit on categorized data. This test is composed of a sum of independent chi 2s, which are applicable only when expectations in each category are not too small. The commonly used approach to solve this problem is to combine classes in order to raise expectations. This, however, means losing some of the information contained in the data and may decrease greatly the power of discrimination between models. A test based on the exact probability distribution of a test statistic, namely the chi 2, has been implemented to avoid this dilemma.

Chi-Square Distribution↗
PubMed1991

Linkage analysis in spinal muscular atrophy, by six closely flanking markers on chromosome 5.

The proximal spinal muscular atrophies (SMA) represent the second most common autosomal recessive disorder, after cystic fibrosis. The gene responsible for chronic SMA has recently been mapped to chromosome 5q by using genetic linkage studies. Among six markers mapping to this region, five were shown to be linked with the SMA locus in 39 chronic SMA families each containing at least two affected individuals. Multilocus analysis by the method of location score was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for SMA is between loci D5S6 and D5S39. The genetic distances between these two markers are estimated to be 6.4 cM in males and 11.9 cM in females. Since meiosis were informative with D5S39 and D5S6 in 92% and 87% of SMA families, respectively, it is hoped that the present study will contribute to the calculation of genetic risk in SMA families.

Chromosome Mapping↗
PubMed1991

Complementation and maternal effect in insulin-dependent diabetes.

The marker association segregation chi-square (MASC) method was applied to a sample of 416 Caucasians affected with insulin-dependent diabetes mellitus (IDDM), for which information on the parental and sibship status was available, as well as HLA typing. We show that the model which best explains all the observations assumes a cis or trans complementation of two tightly linked genes within the HLA region, an additional maternal effect, and other familial factors. The HLA molecule corresponding to the complementation of Arg52(+) and Asp57(-) has been recently proposed as explaining susceptibility to IDDM. However, this hypothesis does not account for the overall observations made on the HLA marker in IDDM patients and their relatives. The MASC method may also be applied to evaluate the risk for relatives of an affected individual (the "index"). For example, the risk for a sib depends not only on the parental status and on the number of HLA haplotypes he shares with the index, but also on which haplotype the index himself inherited from his mother and father.

Diabetes Mellitus, Type 1↗
PubMed1990

Assessing the effect of multiple linkage tests in complex diseases.

The significance of a lod score value of 3 is very difficult to assess in linkage studies between a genetic marker and a complex disease. One reason is that multiple tests may have been performed, voluntarily or otherwise. For the same disease, linkage may be tested by different laboratories with several markers under various genetic models and diagnostic schemes for the disease. In such a case, we show that the probability of getting a lod score value of 3 under independent transmission of the disease and the marker may be not negligible.

Female↗
PubMed1990

Hereditary retinoblastoma: can balanced insertion entirely explain the differences of expressivity among families?

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.

Chromosome Aberrations↗
PubMed1990

Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive type 1 (insulin-dependent) diabetic patients.

The susceptibility determinants of Type 1 (insulin-dependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p less than 0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.

Adult↗
PubMed1990

Sampling strategy in linkage studies of affective disorders.

Evidence of linkage in families of bipolar patients has so far been identified with genetic markers on chromosome X and 11. However, replications of these data have not consistently been reported in either case, which favours the hypothesis of genetic heterogeneity. Therefore, we have tried to outline a sampling strategy for linkage replication in affective disorders. We estimated the average number of nuclear families required to replicate X or 11 linkage as a function of the degree of heterogeneity as well as the number to prove heterogeneity given that linkage exists. The results are presented and discussed.

Bipolar Disorder↗
PubMed1990

Two-disease-locus model: segregation analysis using information on two markers in nuclear families. Application to IDDM.

In the present paper, an extension of segregation analysis is proposed using information on the joint segregation of two unlinked markers conditional on the disease status in nuclear families, in order to consider two-locus models with one locus linked to the first marker and the other linked to the second marker. We propose tests for examining evidence for the effect of genes located at these two loci and whether this effect is multiplicative or not. This method is then applied to a sample of IDDM families typed for the HLA and Gm markers to test, in addition to a factor of the HLA region, the potential involvement of the Gm system in the susceptibility to IDDM. The analysis does not provide evidence for such an involvement.

Chromosome Mapping↗
PubMed1989

Genetic analysis of IDDM: summary of GAW5 IDDM results.

This paper summarizes the analyses by participants in the insulin-dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5). The data were obtained from 94 families with two or more IDDM sibs. Topics treated in the Workshop analysis included the following: methods for detecting associations and linkage, the contribution by HLA-linked and -unlinked loci to IDDM susceptibility, the role of subtypes of the serologically defined HLA specificities, the implications of associated diseases other than IDDM in the families, the significance of antibodies to Coxsackie viruses, and of autoantibodies to pancreatic islet cells and insulin, and the use of genetic models to analyze the inheritance of IDDM. There was agreement that an explanation for the data on multiplex IDDM families must include the following features: 1) There is a susceptibility locus (or loci) in the HLA region. 2) The HLA-linked factor(s) are more complex than a single locus with one disease and one nondisease allele. 3) There is additional familial correlation beyond that explained by HLA-linked susceptibility, which may be genetic and/or environmental. With regard to the third feature, IDDM-GAW5 included data on variation in Gm haplotypes and at the insulin gene, two regions unlinked to HLA. However, there was no direct evidence (i.e., from marker segregation) that the additional factor, if genetic, is linked to either Gm or the insulin gene. Nevertheless, a significant difference was found between "diabetic" and "control" insulin genes with respect to frequency of class 1 alleles for the 5' flanking polymorphism, strongly suggesting linkage.

Data Collection↗