Reproducibility and Complications in Gene Searches: Linkage on Chromosome 6, Heterogeneity, Association, and Maternal Inheritance in Juvenile Myoclonic Epilepsy

Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later st...

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Bibliographic Details
Published in:American journal of human genetics 2000-02, Vol.66 (2), p.508-516
Main Authors: Greenberg, David A., Durner, Martina, Keddache, Mehdi, Shinnar, Shlomo, Resor, Stanley R., Moshe, Solomon L., Rosenbaum, David, Cohen, Jeffrey, Harden, Cynthia, Kang, Harriet, Wallace, Sibylle, Luciano, Daniel, Ballaban-Gil, Karen, Tomasini, Livia, Zhou, Guilian, Klotz, Irene, Dicker, Elisa
Format: Article
Language:English
Subjects:
Alleles
Association analysis
Biological and medical sciences
Chromosome Mapping - methods
Chromosomes, Human, Pair 6 - genetics
Extrachromosomal Inheritance - genetics
Fathers
Female
Gene Frequency - genetics
Genetic Heterogeneity
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
HLA-D Antigens - genetics
Humans
Idiopathic generalized epilepsy
Independent male-female recombination fraction
Juvenile myoclonic epilepsy
Linkage analysis
Lod Score
Male
Medical sciences
Molecular Sequence Data
Mothers
Myoclonic Epilepsy, Juvenile - genetics
Nervous system (semeiology, syndromes)
Neurology
Pedigree
Recombination, Genetic - genetics
Reproducibility of Results
RING3
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Summary:Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal male-female recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (θ), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female θs, the LOD score was significantly higher (4.2) at a male-female θ of .5, .01. Although the overall pattern of LOD scores with respect to male-female θ could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.
ISSN:0002-9297
1537-6605
DOI:10.1086/302763