The affected-pedigree-member method of linkage analysis

This paper describes a generalization of the affected-sib-pair method of linkage analysis to pedigrees. By substituting identity-by-state relations for identity-by-descent relations, we develop a test statistic for detecting departures from independent segregation of disease and marker phenotypes. The statistic is based on the marker phenotypes of affected pedigree members only. Since it is more striking for distantly affected relatives to share a rare marker allele than a common marker allele, the statistic also includes a weighting factor based on allele frequency. The distributional properties of the statistic are investigated theoretically and by simulation. Part of the theoretical treatment entails generalizing Karigl's multiple-person kinship coefficients. When the test statistic is applied to pedigree data on Huntington disease, the null hypothesis of independent segregation between the marker locus and the disease locus is firmly rejected. In this case, as expected, there is a loss of power when compared with standard lod-score analysis. However, our statistic possesses the advantage of requiring no explicit assumptions about the mode of inheritance of the disease. This point is illustrated by application of the test statistic to data on rheumatoid arthritis.