Analysis of genetically complex epilepsies

Abstract

During the last decade, great progress has been made in the discovery of genes that influence risk for epilepsy. However, these gene discoveries have been in epilepsies with Mendelian modes of inheritance, which comprise only a tiny fraction of all epilepsy. Most people with epilepsy have no affected relatives, suggesting that the great majority of all epilepsies are genetically complex: multiple genes contribute to their etiology, none of which has a major effect on disease risk. Gene discovery in the genetically complex epilepsies is a formidable task. It is unclear which epilepsy phenotypes are most advantageous to study, and chromosomal localization and mutation detection are much more difficult than in Mendelian epilepsies. Association studies are very promising for the identification of complex epilepsy genes, but we are still in the earliest stages of their application in the epilepsies. Future studies should employ very large sample sizes to ensure adequate statistical power, clinical phenotyping methods of the highest quality, designs and analytic techniques that control for population stratification, and state-of-the-art molecular methods. Collaborative studies are essential to achieve these goals.

FIG. 1

Expected population distribution of a quantitative trait caused by the additive effects of one, two, or three genes, each with two equally frequent alleles (locus A with alleles A and a, locus B with alleles B and b, and locus C with alleles C and c). The phenotype is determined by the number of alleles denoted by “capital letters” an individual inherits. A: the trait is caused by a single gene “A,” and the phenotype is 0 in aa, individuals, 1 in Aa individuals, and 2 in AA individuals. B: the trait is caused by two genes “A” and “B,” and the phenotype is 0 in aabb individuals, 1 in Aabb or aaBb individuals, 2 in AAbb, AaBb, or aaBB individuals, 3 in AABb or AaBB individuals, and 4 in AABB individuals. C: the trait is caused by three genes “A,” “B,” and “C,” and the phenotype ranges from 0 in aabbcc individuals to 6 in AABBCC individuals. As the number of contributing loci increases, the trait distribution in the population more closely approximates a normal distribution.

FIG. 2

Multifactorial-polygenic model. Liability, an unmeasurable quantitative trait, is normally distributed in the population; and individuals with liability above a threshold value are affected. With epilepsy, the threshold could be conceived of as a seizure threshold. (Modified from Fig. 15 in http://www.uic.edu/classes/bms/bms655/lesson11.html).

FIG. 3

Locus heterogeneity and variable expressivity in GEFS+ and related phenotypes.