A confidence-set approach for finding tightly linked genomic regions

As more studies adopt the approach of whole-genome screening, geneticists a re faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-po int analysis by the LOD method is performed to search for signals of linkag e throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance le vel for the fact that multiple tests are being performed. Various recommend ations have been made, but no consensus has emerged. In this article, we pr opose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multi plicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only t o adjust the level of significance according to the number of disease genes -a much smaller number than the number of markers in a genome screen-to ens ure a predetermined genomewide confidence level. Furthermore, our formulati on of the tests enables us to localize disease genes to small genomic regio ns, an extremely desirable feature that the traditional LOD method lacks. O ur simulation study shows that, for sib-pair data, even when the coverage p robability of the confidence set is chosen to be as high as 99%, our approa ch is able to implicate only the markers that are closely linked to the dis ease genes.