ASSOCIATION MAPPING OF DISEASE LOCI, BY USE OF A POOLED DNA GENOMIC SCREEN

Genomic screening to map disease loci by association requires automati on, pooling of DNA samples, and 3,000-6,000 highly polymorphic, evenly spaced microsatellite markers. Case-control samples can be used in an initial screen, followed by family-based data to confirm marker assoc iations. Association mapping is relevant to genetic studies of complex diseases in which linkage analysis may be less effective and to cases in which multigenerational data are difficult to obtain, including ra re or late-onset conditions and infectious diseases. The method can al so be used effectively to follow up and confirm regions identified in linkage studies or to investigate candidate disease loci. Study design s can incorporate disease heterogeneity and interaction effects by app ropriate subdivision of samples before screening. Here we report use o f pooled DNA amplifications-the accurate determination of marker-disea se associations for both case-control and nuclear family-based data-in cluding application of correction methods for stutter artifact and pre ferential amplification, These issues, combined with a discussion of b oth statistical power and experimental design to define the necessary requirements for detecting of disease loci while virtually eliminating false positives, suggest the feasibility and efficiency of associatio n mapping using pooled DNA screening.