| In human genetic linkage analysis, replication of a previously significant or suggestive finding is an important step in mapping susceptibility trait loci. However, for a complex disorder, the linkage signal is often weak due to incomplete penetrance, phenocopies, locus heterogeneity, etc. (Lander, E. S. & Schork, N. J. (1994). Genetic dissection of complex traits. Science, 265, 2037–2048) which makes the detection of linkage hard and the replication of a previous finding even harder (Suarez, B., Hampe, C. & Van Eeerdeweigh, P. (1994). Problems of replicating linkage claims in psychiatry. In E. S. Gershon & C. R. Cloninger (Eds.), Genetic approaches to mental disorders. American Psychiatric Press, Inc., Washington, DC.; Lander, E. & Kruglyak, L. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics, 11, 241–247).; The main stream of the current methods takes a frequentist approach to analyze data. However, “we should really like to know, at the end of study, the probability that we have found a linkage, as pointed out by Cedric Smith (1959) > 35 years ago.” (Elston, R. C. (1997). Algorithms and inferences: the challenge of multifactorial diseases (1996 William Allen award address). Am. J. Hum. Genet., 60, 255–62). Frequentist approaches are not amenable for this purpose.; We develop a Bayesian approach, called sequential Bayes method, to analyze data from replication studies, allowing for the presence of locus heterogeneity. In this framework, posterior probability of linkage (PPL) is obtained naturally. Point estimate and interval estimate of recombination fraction are proposed. The consistency of PPL, with and without linkage, is proved. This method provides another way to assess evidence of linkage across several studies.; The performance of this method is studied using simulated affected-sib-pair data and simulated general pedigree data. This method is then applied to the data simulated for Genetic Analysis Workshop 11 (GAW 11). Compared to the generating model, this method successfully identified all 4 disease susceptibility loci and mapped these loci with satisfactory accuracy. |
