Researchers in the Family Studies Division are investigating the role of inheritance in neurological disorders, primarily focusing on epilepsy and Alzheimer's disease. In genetic research on epilepsy, one of the most challenging issues is the extreme clinical heterogeneity of the disorder. The clinical variability—with different seizure types, ages at onset, electrophysiologic and neuroanatomic abnormalities, response to treatment, and many other factors—is so striking that most researchers view epilepsy as a collection of different disorders (epilepsies), with different causes. However, the extent to which the different clinical entities also differ with respect to their genetic contributions remains unclear, and hence it is not clear which features are best used to separate the epilepsies into subgroups for genetic research.
In a study published in 2005, Drs. Melodie Winawer, Ruth Ottman, and colleagues examined the genetic relationships among epilepsies with different seizure types within the idiopathic generalized epilepsies: myoclonic, absence, and generalized tonic-clonic. They used a method they developed called "family concordance analysis" to assess the evidence that these three seizure types were influenced by the same, or different genes. By studying families containing multiple individuals with epilepsy collected by their own group and by collaborators in Australia, they found evidence for distinct genetic effects on the three different seizure types. These findings suggest that studies aimed at identifying the genes that influence risk for idiopathic generalized epilepsies may be more powerful if focused on a specific seizure type.
Drs. Joseph Lee, Richard Mayeux, and colleagues are attempting to identify genes that influence risk for late onset Alzheimer's disease. They are studying more than 100 extended families containing two or more affected individuals using a method called "linkage analysis," in which genes evenly spaced over the 23human chromosomes ("genetic markers") are examined systematically to determine whether any are inherited with the disease more often than expected by chance. The co-inheritance of a genetic marker with disease would indicate that a risk-influencing gene is likely to be located within the same chromosomal region as the genetic marker. Using this method, they found strong evidence that a gene on chromosome 18 influences risk for late onset Alzheimer's disease. They also confirmed evidence for genes on chromosomes 10 and 12 that had been previously reported by other research groups. When they followed up the initial findings with additional analyses to zoom in on the locations on chromosomes 18 and 10, the evidence strengthened. Additional work is ongoing to identify which specific genes in these chromosomal regions could influence risk for Alzheimer's disease; several genes in the regions are expressed in the brain and appear to be good candidates. In other work, Lee and Mayeux studied several genetic variant(s)—variations in DNA sequence found commonly in human populations—previously found to be associated with late onset Alzheimer's disease. They found that some variants were associated with both Alzheimer's disease and verbal memory, while others were associated with nonverbal memory alone. This approach of studying the relations of a gene to several related traits may enable them to further disentangle the causes of Alzheimer's disease.