Individual disease risk and multimetric analysis of Crohn disease

Rare dominant genes with high penetrance can be identified by linkage without inbreeding, whereas rare recessive genes with high penetrance are most efficiently recognized by autozygosity mapping of homozygotes in pedigrees with preferential inbreeding. On the contrary, complex inheritance is characterized by common genes with low penetrance, for which family studies and inbreeding are inefficient. Here, we develop the Fisherian theory for diallelic cases and controls, show that it compares favorably with Bayesian estimates, and evaluate their currently low power for discriminating cases and controls in Crohn disease (CD). Significance is enhanced by inclusion of composite likelihood, but identification of causal loci is delayed by low recognition of gene function. Clearly, association mapping is not yet optimal, and so strenuous effort is justified to develop a more inclusive gene map and association tests more powerful than single markers and the current use of composite likelihood. Because of its relatively high heritability and the correspondingly large number of detected causal loci, CD presents an ideal test system to determine the power and flaws of competing methods of whole-genome case/control association analysis in publicly available data. Until such a test is exploited by competing statisticians, their Herculean efforts will be inconclusive, and the costly advances from increased sample size will be suboptimal and disappointing.