Another limitation of GWA studies is their lack of power for identifying associations with rare sequence variants, since these are poorly represented on current genotyping platforms, as are structural variants. The often limited information available on environmental exposures and other nongenetic risk factors in GWA studies will make it difficult to identify gene-environment interactions, or modification of gene-disease associations in the presence of environmental factors. Most variants identified to date are of relatively modest effect size, conferring less than a twofold increase in disease risk and necessitating large sample sizes to detect their effect (9, 34). Although the importance of risk factors with small effect is debated, the potential for purifying selection to eliminate risk variants of large effect is unique to genetic studies and will tend to keep effect sizes small for common variants (53). Modest associations can point the way to important therapeutic avenues, and, when considered in combination, may identify persons at substantially increased risk (28). Such information can be particularly important, even in the absence of specific pharmaceutical agents targeted to such individuals, for more aggressive effortstoreduce known risk factors that are modifiable, such as obesity in prediabetes and smoking in age-related macu-lar degeneration (9).
