Genomic screening and replication using the same data set in family-based association testing

The Human Genome Project and its spin- offs are making it increasingly feasible to determine the genetic basis of complex traits using genome- wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome- wide family- based association studies, using single SNPs or haplotypes, can identify associations that achieve genome- wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease- susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease- susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype- tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome- wide significance, as population- based designs do.