There is more than one way to collect data for linkage analysis. What a study of epilepsy can tell us about linkage strategy for psychiatric disease.

The most popular strategy for finding genes in psychiatric diseases has been to focus on large pedigrees with many affected members. While this strategy has sound advantages, it also has drawbacks that have seldom been addressed. The strategy of using smaller families also has its place in a linkage analysis. To illustrate the point, I discuss herein the successful search for a gene for another common complex disease, namely, idiopathic primary generalized epilepsy. There, investigators in the Los Angeles (Calif) Epilepsy Program used mostly nuclear families who were chosen through a proband with highly specific characteristics. An independent study, using a different strategy but one still focused on small families, then confirmed the linkage. However, investigators of both epilepsy projects put much care into determining which clinical characteristics would be used to define the index cases. The implications for the study of psychiatric disease are as follows: (1) careful attention must be paid to clinical presentation, and (2) there is room for both large-pedigree and small-family strategies in designing linkage studies.