Biomedical subjects

F Clerget-Darpoux

Publications and source records attributed to F Clerget-Darpoux.

At least 73 records · Page 4Linked to original sources

PubMed1997

Variable age at onset in insulin-dependent diabetes mellitus, by the marker-association-segregation-chi 2 method.

The marker-association-segregation-chi 2 (MASC) method with consideration of age, for nonaffected persons, and of age at onset, for affected persons, was applied to a sample of 308 HLA-typed families. Hazard rates modeling the instantaneous risk of catching the disease were estimated under the exponential distribution and with satisfactory goodness of fit. This class of models shows that the hypothesis of the absence of parental imprinting cannot be rejected for insulin-dependent diabetes mellitus.

Age of Onset↗

PubMed1997

No effect of the alpha1-antichymotrypsin A allele in Alzheimer's disease.

The apolipoprotein E (ApoE)-epsilon4 allele is associated in a dose dependent manner to an increased risk for Alzheimer's disease. However, the ApoE-epsilon4 allele effect does not account for all patients with Alzheimer's disease, and the existence of other genetic risk factors has been postulated. Kamboh et al reported an association between Alzheimer's disease and the A allele of alpha1-antichymotrypsin (Aact) gene, which was not confirmed in a larger series more recently analysed. The ApoE and Aact genotypes were analysed in 314 patients with Alzheimer's disease and 173 healthy controls, confirming the dose dependent effect of the ApoE-epsilon4 allele. Nevertheless, even using odds ratios adjusted for age and sex, there was no significant effect of the Aact genotype on Alzheimer's disease or on the ApoE-epsilon4 allele associated risk for Alzheimer's disease.

Alleles↗

PubMed1997

Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women.

Age of Onset↗

PubMed1996

A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years.

We have identified a novel Alzheimer's disease family in which affected subjects had a very young age of onset (range 29-35 years). Neuropathological confirmation of the diagnosis was obtained for one patient. Molecular analysis shows that within this family the disease results from a missense mutation at codon 235 of the presenilin 1 (PS-1) gene. Two patients had exhibited generalized tonico-clonic seizures several years before the onset of dementia. Whether this particular clinical feature is a consequence of the PS-1 mutation remains to be established. The Leu235Pro mutation is, to our knowledge, the PS-1 mutation associated with the youngest age of AD onset, which suggests that it has a drastic effect on PS-1 function.

Adult↗

PubMed1996

Segregation analysis of Alzheimer pedigrees: rare Mendelian dominant mutation(s) explain a minority of early-onset cases. French Alzheimer Collaborative Group.

Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset ( < or = age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands. The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele "a" at a Mendelian dominant gene (MDG). Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in < 20% of probands. Male and female age-of-onset distributions are significantly different for "AA" but not for "aA" subjects. For "aA" subjects the estimated penetrance value was close to 1 by age 60. For "AA" subjects, it reaches, by age 90, 10% (males) and 30% (females). We show a clear cutoff in the posterior probability of being an MDG case.

Age Factors↗

PubMed1996

[Genetics of Alzheimer's disease].

This review reports the different genetic factors that have been identified either as risk factor for Alzheimer's disease (AD) or directly causing the disease. First are reviewed epidemiological data and biological mechanisms about the apoplipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease. The second part describes the mutations responsible for early-onset autosomal dominant AD found in three different genes. The gene located on chromosome 21 encodes the amyloid precusor protein (APP). The presenilin 1 and presenilin 2 genes, located on chromosome 14 and 1 respectively, encode not yet known membrane proteins.

Alzheimer Disease↗

PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗

PubMed1996

No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group.

We sequenced exons 16 and 17 of the APP (amyloid precursor protein) gene in 18 unrelated French Alzheimer's disease (AD) patients. These patients had an onset before the age of 60 and belonged to families with autosomal dominant transmission of the disease. We detected the APP 717 Val-->Ile mutation in three out of 18 (16.6%) families. In these three families, all affected subjects had the APOE 3/3 genotype, but their ages of onset ranged from 38 to 60 years, indicating that factors other than the APOE genotype influence age of onset. Analysis of two polymorphic loci adjacent to the APP gene showed that at least two independent mutational events had occurred within these pedigrees, in spite of their origin in the same region of France.

Adult↗

PubMed1996

Association studies in consanguineous populations.

To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients.

Case-Control Studies↗

PubMed1996

Conclusion of LOD-score analysis for family data generated under two-locus models.

The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to detect a major-gene (MG) effect by segregation analysis and, second, to seek for linkage with genetic markers by the LOD-score method using the MG parameters. We already showed that segregation analysis can lead to evidence for a MG effect for many two-locus models, with the estimates of the MG parameters being very different from those of the two genes involved in the disease. We show here that use of these MG parameter estimates in the LOD-score analysis may lead to a failure to detect linkage for some two-locus models. For these models, use of the sib-pair method gives a non-negligible increase of power to detect linkage. The linkage-homogeneity test among subsamples differing for the familial disease distribution provides evidence of parameter misspecification, when the MG parameters are used. Moreover, for most of the models, use of the MG parameters in LOD-score analysis leads to a large bias in estimation of the recombination fraction and sometimes also to a rejection of linkage for the true recombination fraction. A final important point is that a strong evidence of an MG effect, obtained by segregation analysis, does not necessarily imply that linkage will be detected for at least one of the two genes, even with the true parameters and with a close informative marker.

Alleles↗

PubMed1996

Consanguinity and the sib-pair method: an approach using identity by descent between and within individuals.

To test for linkage between a trait and a marker, one can consider identical marker alleles in related individuals, for instance, sibs. For recessive diseases, it has been shown that some information may be gained from the identity by descent (IBD) of the two alleles of an affected inbred individual at the marker locus. The aim of this paper is to extend the sib-pair method of linkage analysis to the situation of sib pairs sampled from consanguineous populations. This extension takes maximum advantage of the information provided by both the IBD pattern between sibs and allelic identity within each sib of the pair. This is possible through the use of the condensed identity coefficients. Here, we propose a new test of linkage based on a chi2. We compare the performance of this test with that of the classical chi2 test based on the distribution of sib pairs sharing 0, 1, or 2 alleles IBD. For sib pairs from first-cousin matings, the proposed test can better detect the role of a disease-susceptibility (DS) locus. Its power is shown to be greater than that of the classical test, especially for models where the DS allele may be common and incompletely penetrant; that is to say for situations that may be encountered in multifactorial diseases. A study of the impact of inbreeding on the expected proportions of sib pairs sharing 0, 1, or 2 alleles IBD is also performed here. Ignoring inbreeding, when in fact inbreeding exists, increases the rate of type I errors in tests of linkage.

Chromosome Mapping↗

PubMed1995

Evidence for apolipoprotein E epsilon 4 association in early-onset Alzheimer's patients with late-onset relatives.

Recently several reports have extended the apolipoprotein E (APOE) epsilon 4 association found in late-onset Alzheimer's disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset < or = 60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE epsilon 4 allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that for an individual, bearing at least one epsilon 4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases.

Adult↗

PubMed1995

Systematic search of susceptibility loci with methods using gametic disequilibrium.

Susceptibility genes are identified for a simulated complex trait by a systematic genome search for linkage between disease and a genetic marker in the presence of gametic disequilibrium. The transmission/disequilibrium tests TDTa or TDTg for multiallelic markers compare transmitted and nontransmitted alleles or the genotypes formed by the two transmitted alleles and the genotypes formed by the two nontransmitted alleles, respectively. With these two tests we were able to identify the two markers D1G31 and D5G23. Under the simulating model these are in fact two susceptibility genes involved in the disease.

Alleles↗

PubMed1995

Comparing the power of linkage detection by the transmission disequilibrium test and the identity-by-descent test.

The aim of this study is to compare the power of the transmission disequilibrium test (TDT) to that of the identity-by-descent (IBD) distribution test. The relative powers of these tests depend both on the underlying genetic model and on the available family data. Families with two affected sibs are always more informative than those with one affected child and one unaffected child. The IBD test is always more powerful in the first situation and, contrary to the TDT, is independent of the presence of gametic disequilibrium. When there is strong linkage disequilibrium, the TDT can be more powerful than the IBD test. In that case, linkage can be detected by the TDT even in families with only one affected child.

Chromosome Mapping↗

PubMed1995

Modeling the role of two susceptibility loci by the MASC method.

Two susceptibility genes, in linkage disequilibrium with alleles of the markers D1G31 and D5G23, have been identified for the disease in the simulated data set of Problem 1. Here we apply the MASC (marker association segregation chi-square) method to model the joint effect of these two genes, by testing two-locus models. The model we obtain, that is the most parsimonious and that best fits the data, corresponds to a direct involvement of the alleles D1G31-8 and D5G23-7, with a nonmultiplicative effect of the two alleles. This was indeed assumed in the true model used for simulating the data.

Alleles↗

PubMed1995

Statistical properties of the allelic and genotypic transmission/disequilibrium test for multiallelic markers.

The transmission/disequilibrium test (TDT) is extended in two ways for a multiallelic marker: (1) to compare transmitted and nontransmitted alleles from a single heterozygous parent and (2) to compare genotypes formed by the two transmitted alleles and genotypes formed by the two nontransmitted alleles using the information on both parents, heterozygous or not, simultaneously.

Alleles↗

PubMed1995

Posterior probability of linkage and maximal lod score.

To detect linkage between a trait and a marker, Morton (1955) proposed to calculate the lod score z(theta 1) at a given value theta 1 of the recombination fraction. If z(theta 1) reaches +3 then linkage is concluded. However, in practice, lod scores are calculated for different values of the recombination fraction between 0 and 0.5 and the test is based on the maximum value of the lod score Zmax. The impact of this deviation of the test on the probability that in fact linkage does not exist, when linkage was concluded, is documented here. This posterior probability of no linkage can be derived by using Bayes' theorem. It is less than 5% when the lod score at a predetermined theta 1 is used for the test. But, for a Zmax of +3, we showed that it can reach 16.4%. Thus, considering a composite alternative hypothesis instead of a single one decreases the reliability of the test. The reliability decreases rapidly when Zmax is less than +3. Given a Zmax of +2.5, there is a 33% chance that linkage does not exist. Moreover, the posterior probability depends not only on the value of Zmax but also jointly on the family structures and on the genetic model. For a given Zmax, the chance that linkage exists may then vary.

Genetic Markers↗

PubMed1995

Genetic counselling in breast cancer: sensitivity to parameter values and to available information.

Most segregation analyses have concluded that breast cancer results from a mixture of sporadic and genetic cases. Genetic cases are probably due to a rare inherited mutation with autosomal dominant transmission. The lifetime risk for female mutation carriers is close to 1, ten fold greater than for noncarriers. Beyond these accepted results, studies differ in the estimated parameters specifying the correspondence between phenotypes and genotypes. We show here that these differences have an impact on the estimation of the probability that a woman is carrying a mutation given her disease status and also given the information on the disease status of her family members. We illustrate this problem by computing the probability of being a mutation carrier for 16 women (9 affected, 7 unaffected) belonging to one pedigree, using three sets of parameter values. For two of the women, the probability that they inherited the mutation is low, but it varies considerably according to the set of parameter values. For one woman, the probability varies from 20 to 60% if familial information is taken into account. Segregation of 17q markers in families may provide additional information depending on the posterior probability of linkage. Indeed in the pedigree studied here, the segregation of 17q markers provided additional information which moreover decreased the sensitivity to the parameters values. However, the decrease in sensitivity will only be observed if the posterior probability of linkage of the family to the studied markers is high.

Adult↗