Accumulating quantitative trait linkage evidence across multiple datasets using the posterior probability of linkage.

Abstract

Genome scans for complex disorders are frequently inconclusive, prompting researchers to increase sample size in an effort to obtain stronger evidence. However, increasing sample size in the presence of locus heterogeneity may actually, on average, decrease the linkage signal at a true susceptibility gene. The posterior probability of linkage, or PPL, was specifically designed to address this issue in the context of categorical trait analysis, by appropriately accumulating evidence either for or against linkage as new data are added. We now formulate a quantitative trait (QT) analog, the QT-PPL, which directly measures the evidence that a QT is linked to a genetic marker or location. The new QT-PPL is based on a classical single-locus QT likelihood with the trait parameters (allele frequency, genotypic means and variances) integrated out. We show using simulations that the QT-PPL is robust to two key modeling violations (multiple trait loci and non-normality in the form of excess kurtosis), as well as being inherently ascertainment corrected, and illustrate the advantages of the QT-PPL for accumulating linkage evidence across multiple sets of data compared to other QT linkage methods.