Can we increase the likelihood of success for future association studies in epilepsy?

Recently, association studies have become a popular tool to elucidate the genetic basis of diseases that show a high familial recurrence rate but probably are not caused by one single gene. These diseases, like many of the common forms of idiopathic generalized epilepsy, are thought to be caused by several interacting genes, with perhaps also an environmental component to the disease mechanisms. Each of these genes is supposed to have only a small effect and is neither necessary nor sufficient to cause epilepsy by itself. Association studies are considered to be a better tool to detect those genes of small effect than, for example, linkage studies (Risch and Merikangas, 1996). Genetic association is observed at a population level by assessing correlations between genetic variants and the epilepsy phenotype reflecting the original genotype (haplotype/ genetic makeup) of a single founder that has been altered by historical recombinations. However, proof that association indeed exists would need replication of the original findings in independent samples, and ultimately, demonstration that the associated allele(s) can contribute to the disease phenotype by altering biological functions (Colhoun et al., 2003). We expect the number of association studies in epilepsy to increase in the future because of the relative ease of collecting subjects (only patients and healthy controls are needed compared to whole families in linkage studies) and determining genetic variants (high through-put facilities can process thousands of genotypes per day at ever decreasing costs). The expanding use of this association approach raises several issues, some of them exemplified by the