There appears to be little overlap between the regions of strongest linkage and association in this study. A more detailed assessment of SNP and haplotype association in the most significant linkage regions did not yield common variation that could explain the evidence for linkage (Supplementary Table 6). This is an expected outcome if linkage signals arise from rare, high penetrance variation (for which the genotyping arrays do not offer an adequate proxy) while association is sensitive to common variation with lower penetrance (that cannot be detected by linkage). For example, a 0.3% variant that increases risk by 10-fold would readily be picked up by this informative linkage scan, but would very likely not be assessed by the common SNPs on the Affymetrix 5.0 array; by contrast, the modest and protective impact of the 5% variant at the SEMA5A rs10513025 creates no detectable excess allele sharing among siblings but is strongly detected by association.
