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 identify ing specific chromosomal origins of those influences conflict. One early st udy reported that human leukocyte antigen (HLA) markers were genetically li nked to juvenile myoclonic epilepsy (JME); this was confirmed in a later st udy. Other reports did trot 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 s core 2.5), but at a high recombination fraction (theta), suggesting heterog eneity. When linkage analysis was redone to allow independent male-female t heta s, the LOD score was significantly higher (4.2) at a male-female theta of .5, .01. Although the overall pattern of LOD scores with respect to mal e-female theta could not he explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might expla in it. By analyzing loci between HLA-DP and KLA-DR and stratifying the fami lies 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 wit h the linked form. These data also suggest that JME may be predominantly ma ternally inherited and that the HLA-linked form is more likely to occur in families of European origin.