Sample size requirements to control for stochastic variation in magnitude and location of allele-sharing linkage statistics in affected sibling pairs.

Typically, genome scans for complex disease have produced linkage peaks which have proved difficult to replicate in additional independent studies. Here we confirm that this may be due to the large variance in magnitude and position of the linkage statistics when maximized across a region. Simulations suggest that for genes of moderate effect (locus-specific sibling relative risks lambda s in the range 1.23-1.39), sample sizes of less than 500 affected sib pairs will give unacceptably large standard errors in the magnitudes and locations of significant linkage results. For genes of small effect (lambda s < or = 1.13), sample sizes in the region of 1000-2000 pairs may be required to achieve consistency of results between different studies. These figures have important implications for our confidence in location estimates for disease genes obtained from linkage studies of modest size. In particular, collection of larger data sets and/or analysis strategies such as conditioning or narrowing the phenotype definition, in order to increase the relative effect size, may be required before embarking on positional cloning.