Study design issues are summarized in Table 3. A GWAS sample, selected based on a well-defined, heritable phenotype, might include case (ill) and control subjects, subjects with a range of values for a continuous phenotypic variable, or probands and both of their parents (trios) or other constellations of relatives. Samples are often limited to a single ancestry (European, Asian, etc.), because some SNPs have markedly different frequencies across populations (and some are not observed in every population), so that some associations can best be detected in homogeneous samples. Each subject is genotyped using a GWAS SNP array. Extensive “quality control” (data cleaning) is required to detect problems that can result in false negative or false positive findings, such as SNPs and DNA specimens that gave poor quality results, or unexpected relatedness among subjects. Case-control differences in ancestry (”population substructure”) can also confound association test results, but this can be corrected statistically based on correlations among SNP genotypes that reflect ancestry. (38) Most studies then test each SNP for association of genotypes to the phenotype, and impute the genotypes of other HapMap SNPs, based on the correlations among SNPs in HapMap data. (39-41)
