It is sometimes forgotten that linkage studies provide information about rare, relatively penetrant susceptibility loci. Family-based designs are typically not well powered to detect the small effects found in GWASs. For example, on average, siblings share 50% of their genome. Where two siblings have the same disease, departure from this 50% sharing indicates regions that harbor risk variants; but since the SD for sharing is large (approximately 3.7%), large sample sizes are required to detect a significant departure. Family designs can however detect one form of genetic variation that is hidden from GWASs: the joint effect of independent, rare, mutations in the same gene (recall that GWASs are effective for common variants). In a linkage study, the effects of independent mutations will combine together, since the unit of analysis in linkage (the average distance between recombinations in the human genome in a single meiosis) is a much larger genomic region than is the case for association analyses. In cases in which linkage asserts that there is an effect but association fails to detect one, then one explanation is allelic heterogeneity: multiple effects exist in the gene but on different haplotypes.
