Case-control studies with affected sibships

Related cases may be included in case-control association studies if correlations between related individuals due to identity-by-descent (IBD) sharing are taken into account. We derived a framework to test for association in a case-control design including affected sibships and unrelated controls. First, a corrected variance for the allele frequency difference between cases and controls was directly calculated or estimated in two ways on the basis of the fixation index FST and the inbreeding coefficient. Then the correlation-corrected association test including controls and affected sibs was carried out. We applied the three strategies to 20 candidate genes on the Genetic Analysis Workshop 15 rheumatoid arthritis data and to 9187 single-nucleotide polymorphisms of replicate one of the Genetic Analysis Workshop 15 simulated data with knowledge of the "answers". The three strategies used to correct for correlation give only minor differences in the variance estimates and yield an almost correct type I error rate for the association tests. Thus, all strategies considered to correct the variance performed quite well.