Linkage analysis involves performing significance tests at many loci located throughout the genome. Traditional criteria for declaring a linkage statistically significant have been formulated with the goal of controlling the rate at which any single false positive occurs, called the genomewise error rate (GWER). As complex traits have become the focus of linkage analysis, it is increasingly common to expect that a number of loci are truly linked to the trait. This is especially true in mapping quantitative trait loci (QTL), where sometimes dozens of QTL may exist. Therefore, alternatives to the strict goal of preventing any single false positive have recently been explored, such as the false discovery rate (FDR) criterion. Here, we characterize some of the challenges that arise when defining relaxed significance criteria that allow for at least one false positive linkage to occur. In particular, we show that the FDR suffers from several problems when applied to linkage analysis of a single trait. We therefore conclude that the general applicability of FDR for declaring significant linkages in the analysis of a single trait is dubious. Instead, we propose a significance criterion that is more relaxed than the traditional GWER, but does not appear to suffer from the problems of the FDR. A generalized version of the GWER is proposed, called GWERk, that allows one to provide a more liberal balance between true positives and false positives at no additional cost in computation or assumptions.
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