GWAS were initially designed to focus on the higher end of the frequency-effect size spectrum, so much work remains to be done, both in finding other variants in the lower frequency and larger effect domains shown in Fig. 1, and in understanding their functional and pathophysiological properties. To the extent that there are several causal variants on a common haplotype or that causal variants are in imperfect linkage disequilibrium with genotyped markers, marker SNPs will underestimate the associated disease risk.
