Semiparametric linkage analysis using pseudolikelihoods on neighbouring sets

Abstract

For many complex diseases, study has suggested that the disease genes influence not only the occurrence of the disease, but also the age of onset. Current methods in linkage analysis are mainly concentrated on affected relative pairs or affected family members, and age of onset information is either ignored or is taken into account by specifying age-dependent penetrances for liability classes. In fact, affected relatives with different ages of onset may be the result of different genetic aetiologies and unaffected relatives are censored at the study time. Therefore, incorporation of age of onset and including contrasts between affected and unaffected pedigree members are important components of effective analysis for the detection of linkage with genetic markers. We use multiple markers to infer the inheritance vector in order to extract information about the inheritance pattern of the disease allele in a pedigree. For a given inheritance vector, we define two neighbour sets for each individual based on allele identical by descent (IBD). We then use the within-set and between-sets conditional hazard ratios to characterize the dependence of age of onset among relatives. A pseudolikelihood ratio test is proposed for testing linkage. Simulated and real data sets are used to illustrate these new statistical methods.