About the use of APOE in Alzheimer's disease studies.
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Alzheimer Disease↗
Biomedical subjects
F Clerget-Darpoux
Publications and source records attributed to F Clerget-Darpoux.
Apolipoprotein E epsilon4 allele and familial aggregation of Alzheimer disease.
OBJECTIVE: To investigate the relationship among risk for Alzheimer disease (AD), familial aggregation of AD, and the apolipoprotein E (apoE) epsilon4 allele in first-degree relatives of probands with AD and known apoE genotype. PATIENTS: Two hundred ninety subjects fulfilling the criteria of the National Institute of Neurological Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were ascertained from March 1, 1992, to December 31, 1996, through consecutive admissions in several university hospitals. DESIGN AND METHODS: Family data were collected on 1176 first-degree relatives (parents and siblings), aged 40 to 90 years. Most living relatives underwent a clinical examination, whereas we relied on family history for clinical data for deceased or unavailable relatives. First, we conducted standard survival analyses to estimate cumulative lifetime risk (LTR) for AD among relatives and to investigate for sex and apoE genotype effects on LTR. Then, we assessed to what extent clustering of secondary AD could be explained by the apoE epsilon4 allele by deriving the expected proportions of relatives with 0, 1, or 2 apoE epsilon4 alleles conditionally on the proband's genotype. RESULTS: Cumulative LTR for AD among first-degree relatives increased significantly with the number of epsilon4 alleles present in the proband. By 90 years of age, LTRs in relatives of probands with epsilon3/epsilon3, epsilon3/epsilon4, and epsilon4/epsilon4 genotypes were 29.2%, 46.1%, and 61.4%, respectively. Significant sex-by-apoE genotype interaction effects on LTR were observed. Women had about a 2-fold higher risk for AD than men among relatives of epsilon4 carriers but not among relatives of non-epsilon4 carriers. The predicted proportion of epsilon4 carriers in relatives of probands with epsilon3/epsilon3 genotype remains about 50% lower than the corresponding LTR for AD, indicating that familial clustering of AD is largely due to other factors than the apoE epsilon4 allele. Although aggregation of AD in families of probands with the epsilon4 allele is more prominent, we estimated that AD would not develop in about 30% of female and up to 60% of male relatives carrying at least 1 epsilon4 allele, even by 90 years of age. CONCLUSION: Our results support the hypothesis that the apoE epsilon4 allele enhances AD susceptibility, but putative factors enhancing risk for AD remain to be found.
Adult↗
Modelling the major histocompatibility complex susceptibility to RA using the MASC method.
To explain the association between HLA-DRB1 gene and rheumatoid arthritis (RA), two main hypotheses have been proposed. The first, the shared epitope hypothesis, assumes a direct role of DRB1 in RA susceptibility. The second hypothesis assumes a recessive disease susceptibility gene in linkage disequilibrium with DRB1. To investigate these two hypotheses, we analysed data on the HLA-DRB1 and TNF-LT loci in 49 affected sib-pairs. We used the Marker Association Segregation Chi-square (MASC) method in which the genotype distribution of markers among index cases and the haplotype sharing in affected sib-pairs are jointly taken into account. With DRB1 data alone, both hypotheses were shown to fit but with analysis of TNF data, both hypotheses were strongly rejected. Thus the TNF data provided additional information for a better understanding of genetic susceptibility to RA than was previously possible using only HLA-DR data. A theoretical standpoint is addressed here on the advisability of using different linked markers in a candidate region for modelling the contribution of this region in disease susceptibility.
Adolescent↗
Optimization of genome search strategies for homozygosity mapping: influence of marker spacing on power and threshold criteria for identification of candidate regions.
Mapping of genes involved in rare recessive diseases is usually difficult because of the lack of families with more than one affected progeny. The problem may be avoided by using inbred affected individuals and the strategy of homozygosity mapping. In practice, the use of homozygosity mapping in a genome-wide scan requires that a set of markers regularly spaced and spanning the whole genome are tested. Investigators are then faced to the problem of choosing the spacing of markers. To help solve this problem, we give some useful clues by computing (1) the expected length of the region of identity by descent around the disease locus, (2) the distribution, given the spacing of markers, of the number of affected individuals expected not to be homozygous at the marker closest to the disease locus and, (3) the expected type-one error. We show that even if the markers are very closely spaced, it is not unlikely that some affected individuals in the sample will not be homozygous at the marker closest to the disease locus. Excluding a region by the criterion that all affected individuals in the sample are not homozygous may then dramatically increase the rate of false negatives. We thus propose to relax the criterion to declare a region candidate, based on the sample size and the spacing of markers.
Chromosome Mapping↗
Overview of strategies for complex genetic diseases.
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Diabetes Mellitus, Type 1↗
Genome search in celiac disease.
Celiac disease (CD), a malabsorption disorder of the small intestine, results from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the entire genetic susceptibility. To determine the localization of other genetic risk factors, a systematic screening of the genome has been undertaken. The typing information of 281 markers on 110 affected sib pairs and their parents was used to test linkage. Systematic linkage analysis was first performed on 39 pairs in which both sibs had a symptomatic form of CD. Replication of the regions of interest was then carried out on 71 pairs in which one sib had a symptomatic form and the other a silent form of CD. In addition to the HLA loci, our study suggests that a risk factor in 5qter is involved in both forms of CD (symptomatic and silent). Furthermore, a factor on 11qter possibly differentiates the two forms. In contrast, none of the regions recently published was confirmed by the present screening.
Celiac Disease↗
On the probability of identity states in permutable populations: reply to Cannings.
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Genetics, Population↗
A gene for Meckel syndrome maps to chromosome 11q13.
Meckel syndrome (MKS) is a rare autosomal recessive lethal condition of unknown origin, characterized by (i) an occipital meningo-encephalocele with (ii) enlarged kidneys, with multicystic dysplasia and fibrotic changes in the portal area of the liver and with ductal proliferation, and (iii) postaxial polydactyly. A gene responsible for MKS in Finland has been mapped to chromosome 17q21-q24. Studying a subset of Middle Eastern and northern African MKS families, we have recently excluded the chromosome 17 region and have suggested a genetic heterogeneity. In the present study, we report on the mapping of a second MKS locus (MKS2) to chromosome 11q13, by homozygosity mapping in seven families that do not show linkage to chromosome 17q21-q24 (maximum LOD score 4.41 at recombination fraction .01). Most interestingly, the affected fetuses of southern Tunisian ancestry shared a particular haplotype at loci D11S911 and D11S906, suggesting that a founder effect is involved. Our observation gives support to the clinical and genetic heterogeneity of MKS.
Abnormalities, Multiple↗
Lack of correlation between genotype and phenotype in celiac disease.
BACKGROUND: Celiac disease has a wide range of clinical features. The goal of this study was to evaluate whether specific HLA genotypes are associated with particular clinical appearances. METHODS: One hundred forty-five patients with confirmed celiac disease were oligotyped for DR and DQ HLA genes. Clinical notes, physical examination, and a questionnaire provided their personal data. Patients were grouped into nine genotypic categories, according to the presence of the specific DQ heterodimer DQA1*0501-DQB1*0201 (hence termed alpha0beta0), in single or double dose, and the presence of the DRB4 antigen. RESULTS: Age at first symptoms and age at beginning of gluten-free diet were not significantly different in the nine groups. The initial symptoms of the disease had a similar distribution in all groups. In twenty-seven patients, disease was diagnosed by family screening: they shared a similar HLA genotype with those who had relevant symptoms. The actual growth status-evaluated by standardized height, percentage of median weight for age, and percentage of median weight for height--was not different in the nine groups. Presence of unusual health complaints was not associated with a specific genotype. CONCLUSIONS: There is no evidence that clinical features of celiac disease are associated with different HLA genotypes. Genes outside the HLA may play a relevant role.
Body Height↗
De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group.
The presenilin 1 (PS1) gene, located on chromosome 14, is the major gene involved in the autosomal dominant forms of early onset Alzheimer's disease (AD). In order to estimate the frequency of de novo PS1 mutations, we have sequenced the PS1 open reading frame in 13 clinically diagnosed patients with no affected relatives, who had developed AD before the age of 50. In one case with onset at 37 years, we identified a missense mutation resulting in a methionine to lysine substitution at codon 139 of the PS1 gene. This substitution is the fourth identified at the same codon. This study, in agreement with previous reports, suggests that de novo PS1 mutations can occur but at a low frequency.
Adult↗
A systematic study of oligodendrocyte growth factors as candidates for genetic susceptibility to MS. French Multiple Sclerosis Genetics Group.
OBJECTIVE: To test 23 genes coding for growth factors and their receptors as candidates for MS genetic susceptibility in 84 multiplex families of French origin by linkage analysis. BACKGROUND: Epidemiologic studies have indicated that genetic susceptibility in MS exists. To identify MS susceptibility genes, association and linkage studies were performed with candidate genes suggested by the pathology of MS. The most consistent result was genetic association and linkage of MS to human leukocyte antigen (HLA) DR15. Recent advances in the knowledge of MS pathology have suggested that the oligodendrocyte, the myelin-forming cell in the CNS, and its growth factors might play a crucial role in MS. METHODS: Fifty-two polymorphic markers within or flanking 23 candidate genes were used. Data were analyzed with the maximum likelihood score (MLS) approach. We also searched for a genetic interaction with HLA. RESULTS: Negative results were obtained for all candidate genes. The lower limits of the relative risk (Xs) possibly excluded for any candidate gene ranged from 1.3 to 2.8. Positive MLS values (up to 0.93) were observed for transforming growth factor beta 3 (TGFbeta3) in HLA DR15-associated families, suggesting a possible role for this growth factor in interaction with HLA. CONCLUSIONS: Oligodendrocyte growth factors do not play a significant role in MS genetic susceptibility, at least in the tested sample. TGFbeta3, the only gene highlighted by this study, deserves further analysis.
Adult↗
[Genetics of Alzheimer's disease].
This review reports epidemiological data and biological mechanisms about the Apolipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease (AD). The second part describes the three genes, amyloid precusor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes, which when mutated cause early-onset autosomal dominant AD. Mutations on each of these genes have as a common consequence elevated levels of A beta (42,3).
Alzheimer Disease↗
Evidence for linkage disequilibrium between HLA-DRB1 gene and multiple sclerosis. The French Research Group on Genetic Susceptibility to MS.
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Genes, MHC Class II↗
Synergistic effect of two HLA heterodimers in the susceptibility to celiac disease in Tunisia.
The DR and DQ HLA genotypes of 94 Tunisian children affected with celiac disease are analyzed so that we can gain a better understanding of the HLA component of this disease. All of them carry at least one of two specific heterodimers: a DQ heterodimer, encoded by DQA1*0501, DQB1*0201 and/or a DR heterodimer, encoded by the nonpolymorphic gene DRA and the DRB4 gene. Quantifying the relative penetrances of all susceptible genotypes gives evidence for a synergistic effect of these two heterodimers and for a dose effect of the alleles encoding the beta chains of these two heterodimers. The DR3DR7 individuals have the greatest risk. They present the two kinds of heterodimers and carry two DQB1*0201 alleles. Celiac disease is the first HLA-associated disease for which the at-risk genotypes are so well delineated.
Adolescent↗
Caution in the interpretation of MLS.
We study the statistical properties of the maximum likelihood score (MLS) test. We show that the criteria for reaching conclusions about linkage are not the same for single point analysis as for multipoint, where the maximization is performed over an additional parameter, the position in the marker interval where the MLS is computed. In addition, this test is shown to be very sensitive to errors in allele frequencies and recombination fraction.
Alleles↗
Heterogeneity of marker allele frequencies hinders interpretation of linkage analysis: illustration on chromosome 18 markers.
In the first part of our study we tested linkage with chromosome 18 markers in a sample of bipolar I sib pairs. We did not obtain evidence for linkage but showed that we could not exclude the presence of a disease locus (having even a non-negligible effect). The limitation of the sib-pair sample size, and consequently of the conclusions, was a result of our care in assuring that the linkage analysis was free of possible errors in the marker allele frequencies. In the second part, we illustrated the possible impact of such heterogeneity in a single data set when applying the multipoint (APM) method. An Amish pedigree included in the study of Berrettini et al. was analyzed under two sets of marker allele frequencies. One set corresponds to estimates from the entire data set and the second to estimates from the Amish pedigree only. Very different values for the APM statistics were obtained. Although the real frequencies are unknown for this family belonging to an isolated population, this example illustrates that heterogeneity in the populations from which familial data are collected may artificially increase evidence for linkage and hinder interpretation of the analysis.
Alleles↗
An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the presence of multiple cartilage-capped exostoses in the juxta-epiphyseal regions of the long bones. EXT is heterogeneous with at least three different locations currently having been identified on chromosomes 8, 11 and 19. We have tested a series of 29 EXT families for possible linkage to the three disease loci and estimated the probability of linkage of the disease to each locus in our series, by using an extension of the admixture test, which makes modelling of heterogeneous monogenic disease feasible. The maximum likelihood was obtained for proportions of 44%, 28% and 28% of families being linked to chromosome 8, 11 and 19, respectively. The a posteriori probability of linkage of the disease to EXT1, EXT2 and EXT3 was greater than 80% for 8/29, 5/29 and 3/29 families, respectively, and did not give evidence of a fourth locus for the disease. The present approach can be generalized to the investigation of genetic heterogeneity in other monogenic diseases, as it simultaneously estimates the location of each disease gene and the proportion of families linked to each locus.
Chromosomes, Human, Pair 11↗
Information provided by pairs of distantly affected relatives to search for genes involved in rare autosomal dominant diseases.
When dominant mutations of different genes may lead to the same disease, it is often difficult to detect in a particular patient which gene is involved. A strategy is to make genealogical extensions to find affected relatives that should have inherited the same mutation. In particular, for diseases with late age of onset or short survival time, only poor information may be obtained from close relatives of probands and it can be particularly efficient to make genealogical extensions to detect pairs of distantly related affected individuals. Such a pair of affecteds may provide information concerning the region of the genome where the mutated gene should map. Two situations may be encountered depending on whether or not prior information on the location of mutated genes involved in the disease are available. If we already know, from previous linkage studies, that a gene located in a given region R of the genome may be involved in the disease, the problem is then to confirm that it is indeed a mutation of this gene that is involved in the affected pair. Once the implication of a gene in region R has been confirmed the affected pair of relatives may give information to restrict the length of this region R. In this paper we discuss these two points by deriving analytically first the lod score expected and second the expected reduction of the length of the region where the mutation is suspected to map as a function of the number of meioses between the two affected individuals and of the polymorphism of the markers available in the region.
Chromosome Aberrations↗