in the exploration of complex disorders. The few linkage studies that are now performed use SNP markers, genotyped in large numbers to match and exceed the high information content of microsatellites. The genetic effect sizes of common alleles uncovered by most GWAS are so small that one would need millions of families to detect them by linkage, which seems to be a justification for favoring GWAS. One, however, needs to be careful when comparing linkage and association. As opposed to association studies, linkage would detect a disease locus with multiple rare disease risk alleles, provided their combined effect is substantial. In view of the most recent GWAS results where the identified variants do not explain much of the heritability of the respective disorders (16), linkage is starting to look attractive again as it could provide target regions for next generation sequencing and allow the inference of mutation segregation across pedigrees, leading to the discovery of disease variants not visible by GWAS.
