Abstract for presentation at 11th International Congress of Human Genetics

Commercial offerings from multiple genetic technology providers make possible whole genome association scans with 100-500K markers. Our experience in conducting large-scale association studies has demonstrated that devising efficient follow-up strategies that can validate associations and characterize the extent of the associated locus are critical for any type of association screen.
In a gene-based screen of 1500 genes including 4500 markers on 311 cases and 311 controls for a common disease, we identified 25 genes of interest for further follow-up. 2027 SNPs were genotyped across the selected gene regions (average of 1 SNP per 13 kb) in the same samples to determine if the association signal in the initial screen was limited to portions of the original gene of interest or extended into regions that may be occupied by flanking genes.
We analyzed this dataset using single point and haplotype methods and summarized our findings about each locus. With the information available for these loci, we investigated the impact of a variety of follow-up study design parameters as well as analysis methods on the conclusions made about the extent of association. The design parameters included how far away from the gene of interest should follow-up genotyping be done, and how to select markers across the loci.
We identified the region to genotype using the extent of linkage disequilibrium estimated in Caucasian HapMap samples between the markers in the original scan and other markers eligible for genotyping. Using a cut-off of r²≥ 0.5 and ≥ 0.2 resulted in similar conclusions. Use of marker selection algorithms reduced the number of markers typed within each region by 50%, while having little effect on the conclusions made about the locus. Efficient strategies for elucidating the extent of association with traits with follow-up genotyping are important and potentially expensive, especially for whole genome association studies.