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M Durner

Publications and source records attributed to M Durner.

15 recordsLinked to original sources
PubMed1997

Exploring linkage of chromosome 18 markers and bipolar disease.

The linkage reports of bipolar disease and chromosome 18 markers are controversial. We used the GAW10 data sets to further explore several observations: 1) a possible parent-of-origin effect with only 'paternal' pedigrees showing linkage; 2) the preponderance of women affected with bipolar disease, and 3) the possible existence of phenocopies in the bipolar data sets. We performed linkage analysis allowing for independent male/female recombination fractions. Our hypothesis was that if there is linkage only in 'paternal' pedigrees, then the lod score would maximize at low male and high female recombination fractions. We did not find such an effect in the combined data set. There was no consistent effect on the difference of male and female recombination fractions, suggesting that an effect is not detectable in this data set with this method. In addition, there is interesting evidence for a recessively inherited, highly penetrant gene in a subset of families. Allowing for higher penetrances for bipolar disease in women than in men had no effect on the lod scores. There was also not much difference in the lod scores calculated under the assumption of a phenocopy rate versus no phenocopies. From simulation studies, we would have expected some effect if there were linkage and phenocopies were present.

Bipolar Disorder↗
PubMed1996

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Chromosome Mapping↗
PubMed1996

Association of HLA class II alleles in patients with juvenile myoclonic epilepsy compared with patients with other forms of adolescent-onset generalized epilepsy.

Reports have suggested an association of juvenile myoclonic epilepsy (JME) with an HLA-DR allele. We examined the HLA-DR and DQ frequencies in two populations of epilepsy patients: (1) JME patients and (2) patients with other forms of adolescent-onset, idiopathic generalized epilepsy (IGE). We did DNA-based HLA typing on 24 JME patients and 24 patients with non-JME forms of adolescent-onset IGE, forms that are clinically similar to JME. In typing the HLA region, we paid particular attention to the alleles contributing to the HLA-DR13 type and also to the DQB1 locus alleles that are in linkage disequilibrium with the alleles that comprise the DR13 type. We also examined the HLA-AP locus, which is centromeric to the DR locus. The frequency of DR13 was significantly higher in JME compared with the non-JME patients. Nine JME patients, compared with two non-JME patients, carried that type (chi 2 = 5.78 [p < 0.017, 1 df]). The odds ratio was 6.6. Furthermore, the DQB1 alleles in linkage disequilibrium with the alleles contributing to the DR13 type were also more frequent in JME than in non-JME epilepsy patients. The chi 2 is highly significant (8.1, p < 0.005) with an odds ratio of 13.8. These results confirm that JME is an HLA-associated form of epilepsy. They also show that the JME locus probably lies within the HLA region, most likely between the HLA-DP and HLA-B loci. The association studies also confirm linkage results showing that JME is genetically different from some other IGEs and emphasize that careful diagnosis is critical to genetic studies of the epilepsies.

Adolescent↗
PubMed1995

Screening for linkage and association in nuclear families.

We applied linkage analysis with a sib-pair method, which also takes into account information on unaffected siblings, and family-based methods of association analysis to determine the disease affecting loci in Problem 1. Whereas the first two disease loci were correctly identified by association analysis, the sib-pair linkage method failed to detect the disease loci 3 and 4. We therefore determined the data structure and sample size necessary for demonstrating linkage to these loci.

Alleles↗
PubMed1995

The genetics of idiopathic generalized epilepsies of adolescent onset: differences between juvenile myoclonic epilepsy and epilepsy with random grand mal and with awakening grand mal.

Both linkage and association studies provide strong evidence that a gene locus on chromosome 6 is involved in the expression of juvenile myoclonic epilepsy (JME), an adolescent-onset form of primary idiopathic generalized epilepsy (IGE). This epilepsy-related gene locus, designated EJM-1, may also influence the expression of other forms of IGE. We report here evidence that at least one form of epilepsy that is similar to JME--pure, adolescent-onset grand mal epilepsy in which the seizures occur at any time during waking--is not linked to the EJM-1 locus. However, we also have evidence that another form of pure, adolescent-onset grand mal that occurs on awakening is linked to the EJM-1 locus and may be genetically the same as JME. This work suggests that clinically similar epileptic syndromes may have different genetic bases and underscores the critical importance of careful clinical observations in studying the genetics of the epilepsies.

Adolescent↗
PubMed1992

Effect of heterogeneity and assumed mode of inheritance on lod scores.

Heterogeneity is a major factor in many common, complex diseases and can confound linkage analysis. Using computer-simulated heterogeneous data we tested what effect unlinked families have on a linkage analysis when heterogeneity is not taken into account. We created 60 data sets of 40 nuclear families each with different proportions of linked and unlinked families and with different modes of inheritance. The ascertainment probability was 0.05, the disease had a penetrance of 0.6, and the recombination fraction for the linked families was zero. For the analysis we used a variety of assumed modes of inheritance and penetrances. Under these conditions we looked at the effect of the unlinked families on the lod score, the evaluation of the mode of inheritance, and the estimate of penetrance and of the recombination fraction in the linked families. 1. When the analysis was done under the correct mode of inheritance for the linked families, we found that the mode of inheritance of the unlinked families had minimal influence on the highest maximum lod score (MMLS) (i.e., we maximized the maximum lod score with respect to penetrance). Adding sporadic families decreased the MMLS less than adding recessive or dominant unlinked families. 2. The mixtures of dominant linked families with unlinked families always led to a higher MMLS when analyzed under the correct (dominant) mode of inheritance than when analyzed under the incorrect mode of inheritance. In the mixtures with recessive linked families, assuming the correct mode of inheritance generally led to a higher MMLS, but we observed broad variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic Linkage↗
PubMed1992

Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of analysis methods.

Heterogeneity, both inter- and intrafamilial, represents a serious problem in linkage studies of common complex diseases. In this study we simulated different scenarios with families who phenotypically have identical diseases but who genotypically have two different forms of the disease (both forms genetic). We examined the proportion of families displaying intrafamilial heterogeneity, as a function of mode of inheritance, gene frequency, penetrance, and sampling strategies. Furthermore, we compared two different ways of analyzing linkage in these data sets: a two-locus (2L) analysis versus a one-locus (SL) analysis combined with an admixture test. Data were simulated with tight linkage between one disease locus and a marker locus; the other disease locus was not linked to a marker. Our findings are as follows: (1) In contrast to what has been proposed elsewhere to minimize heterogeneity, sampling only "high-density" pedigrees will increase the proportion of families with intrafamilial heterogeneity, especially when the two forms are relatively close in frequency. (2) When one form is dominant and one is recessive, this sampling strategy will greatly decrease the proportions of families with a recessive form and may therefore make it more difficult to detect linkage to the recessive form. (3) An SL analysis combined with an admixture test achieves about the same lod scores and estimate of the recombination fraction as does a 2L analysis. Also, a 2L analysis of a sample of families with intrafamilial heterogeneity does not perform significantly better than an SL analysis. (4) Bilineal pedigrees have little effect on the mean maximum lod score and mean maximum recombination fraction, and therefore there is little danger that including these families will lead to a false exclusion of linkage.

Computer Simulation↗
PubMed1992

Evidence for multiple gene loci in the expression of the common generalized epilepsies.

Our knowledge of genetic factors influencing expression of epilepsy has increased enormously in the last 10 years. In this article, we review the advantages and problems of population genetics studies, twin studies, and linkage analysis as applied to the study of epilepsy. Population genetics, twin studies, and linkage analysis have placed the evidence for the genetic basis of the generalized epilepsies on a firm foundation. The identification and confirmation of a gene locus involved in the expression of juvenile myoclonic epilepsy and other forms of generalized epilepsy is proof of at least one genetic influence. We also review the evidence that other, still-undiscovered genetic factors might influence the expression of other forms of generalized epilepsy.

Brain↗
PubMed1992

Is there a genetic relationship between epilepsy and birth defects?

Children of epileptic mothers have a greater risk for congenital malformations than is seen in the general population. This risk has been attributed mostly to teratogenic effects of antiepileptic drugs, but other risk factors have been suggested, such as epilepsy, per se, or some underlying genetic defects associated with epilepsy. Previous studies do not answer the question of whether genetic factors contribute to the high risk of malformations in children of epileptic parents. Genetic studies in families of patients with neural-tube defects and cleft lip (CL), with and without cleft palate (CP), as well as genetic studies in families of patients with epilepsy, show evidence for the possible existence of genes on the short arm of chromosome 6. The suspected gene for CL and CP is linked to factor XIIIa and is neither identical with or linked to a gene for idiopathic generalized epilepsy, which is close to the HLA region. The short arm of chromosome 6 also contains a human homologue of the mouse t-complex. Alterations of the mouse t-complex are involved in defects of neural-crest development in mice. Relationships between a human homologue of the mouse t-complex, epilepsy, and birth defects have yet to be proven.

Abnormalities, Drug-Induced↗
PubMed1991

Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6.

Juvenile myoclonic epilepsy (JME) is a generalized, non-progressive epilepsy characterized by an adolescent onset of sudden, involuntary myoclonic jerks. Greenberg et al. (American Journal of Medical Genetics 31:185-192, 1988b; Cytogenetics and Cell Genetics 51:1008, 1989b) reported tight linkage of a JME locus to the HLA region of chromosome 6p. We confirm this linkage assignment, although at a larger recombination fraction than previously reported. Twenty-three, mostly nuclear, families were ascertained through a JME proband. The affected status of relatives of the probands was assigned by 4 different clinical criteria, and separate analyses were done assuming an autosomal dominant model with 90% penetrance and an autosomal recessive model with full penetrance. A linear age-of-onset correction with maximum penetrance at age 20 years was incorporated into the analyses. The maximum lod score obtained was 3.11 at (-)m = 0.001, (-)f = 0.20, assuming autosomal dominant inheritance and using the second definition of the disease phenotype. There was strong support for linkage using the other phenotype definitions and the autosomal dominant model, although the lod scores did not exceed 3.0. There was also support for linkage of a JME locus to this region under the autosomal recessive model, although the results varied depending upon the definition of the disease phenotype. There was no significant evidence for linkage heterogeneity.

Chromosome Mapping↗
PubMed1991

Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients.

Juvenile myoclonic epilepsy (JME) is a distinct subform of idiopathic generalized epilepsy of adolescence. Linkage studies with Bf and serologic HLA markers in families of JME patients have shown a tight linkage on chromosome 6. We present a linkage analysis with HLA-DQ restriction fragment length polymorphisms on more extended families, paying particular attention to the epilepsy type of the affected family members. We studied 21 families of JME patients with a total of 143 family members and obtained a highest logarithm of the odds (lod) score of 3.9 (theta m = 0.01, theta f = 0.01) assuming a dominant mode of inheritance and 70% penetrance when family members with JME, absence epilepsy, or epilepsy with generalized tonic-clonic seizures (GTCS) were considered as affected. When we also classified clinically normal family members with generalized spike-wave discharges in the EEG as "affected," the maximum lod score was 4.1 (theta m = 0.01, theta f = 0.3) under a dominant mode of inheritance and 90% penetrance. These findings support the conclusion that a gene locus for a group of idiopathic generalized epilepsies (JME, epilepsy with absences, and epilepsy with GTCS) maps to chromosome 6p.

Chromosomes, Human, Pair 6↗
PubMedDate not supplied

Possible association of juvenile myoclonic epilepsy with HLA-DRw6.

Juvenile myoclonic epilepsy (JME) is a clearly defined subform of idiopathic generalized epilepsy with a high aggregation of epilepsy in family members. With the HLA-system used as a genetic marker, a linkage between JME and the HLA region was demonstrated. Linkage with the HLA region suggests that JME may be associated with an HLA-antigen. An association could indicate that the gene lies in the HLA region and is in linkage disequilibrium with one of the HLA-antigens. Eighty-eight unrelated patients with JME were typed for the HLA-A and HLA-B locus, 77 were typed for the HLA-C locus, and 76 were typed for the DR locus. The antigen frequency was compared with those of healthy blood donors. The highest difference was noted in the frequency of DRw6 (39.5% in patients vs. 22.1% in controls). This weak association is open to question because DRw6 is known to split into DRw13 and DRw14.

Epilepsies, Myoclonic↗
PubMedDate not supplied

Phenocopies versus genetic heterogeneity: can we use phenocopy frequencies in linkage analysis to compensate for heterogeneity?

In this study we explore whether a phenocopy frequency (defined as a "penetrance' for nondisease genotypes) can approximate or model genetic heterogeneity in a single-locus analysis. We simulated two types of heterogeneity situations: "sporadic models', where there are two forms of a disease, one genetic and linked to a marker and the other purely random, and "genetic heterogeneity models', where the disease is caused by either of two different loci, one linked to the marker and the other unlinked. We analyzed simulated data sets for linkage, assuming a single-locus analysis with varying phenocopy frequency, in analogy with earlier work on epistatic two-locus models. We found that in the presence of purely random sporadics, there was a difference between assuming any nonzero phenocopy frequency and a zero frequency, but that the actual value of the assumed phenocopy frequency had little effect on the maximum lod score. In contrast, when both forms of disease are genetic, and are generated under similar genetic parameters, assuming a positive phenocopy frequency will not, in general, compensate for the presence of the unlinked form. However, when the modes of inheritance of the two forms differ, the assumption of a nonzero phenocopy frequency does have an effect, either to increase or decrease the maximum lod score, depending on the modes of inheritance of the two disease forms. We conclude with practical recommendations for investigators, based on these results.

Gene Frequency↗