Reproducibility and complications in gene searches: Linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy

David A. Greenberg, Martina Durner, Mehdi Keddache, Shlomo Shinnar, Stanley R. Resor, Solomon L. Moshe, David Rosenbaum, Jeffrey Cohen, Cynthia Harden, Harriet Kang, Sibylle Wallace, Daniel Luciano, Karen Ballaban-Gil, Livia Tomasini, Guilian Zhou, Irene Klotz, Elisa Dicker

Research output: Contribution to journalArticle

106 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)508-516
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Jan 1 2000


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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