The frequency with which an allele occurs in the population and the risk incurred by that allele for complex diseases are key components to consider when planning a genetic study, impacting the technology needed to gather genetic information and the sample size needed to discover statistically significant genetic effects. The spectrum of potential genetic effects is sometimes visualized and partitioned by effect size and allele frequency (figure 1). Genetic effects in the upper right are more amenable to smaller family-based studies and linkage analysis, and may require genotyping relatively few genetic markers. Effects in the lower right are typical of findings from GWAS, requiring large sample sizes and a large panel of genetic markers. Effects in the upper right, most notably CFH, have been identified using both linkage analysis and GWAS. Effects in the lower left are perhaps the most difficult challenge, requiring genomic sequencing of large samples to associate rare variants to disease.
