Assessing the contribution family data can make to case-control studies of rare variants

When pathogenic variants are rare then even among cases the proportion of subjects possessing a variant might be low, meaning that very large samples might be required to conclusively demonstrate evidence of an effect. Relatives of subjects within a case-control sample might provide useful additional information. The method of model-free linkage analysis implemented in MFLINK was adapted to incorporate linkage disequilibrium (LD) parameters in order to test for an effect of a putative pathogenic variant in complete LD with a disease locus. The effect of adding in to the analysis relatives of cases and controls found to carry the variant was investigated. When affected siblings or cousins of cases possessing the variant were incorporated they had a large effect on the results obtained. The evidence for involvement increased or reduced as expected, depending on whether or not the relatives themselves were found to possess the variant. The size of the effect was large relative to that expected from just increasing the size of a standard case-control sample. Affected relatives offer a valuable resource to assist the interpretation of case-control studies of rare variants. The method is capable of including other relative types and can deal with complex pedigrees.