Figure 1. Frequency of genetic variation and disease susceptibility.

Figure adapted from references 112,113

A portion of “missing heritability” may be explained by low frequency variants with intermediate penetrance. The low risk-allele frequencies make the variants undetectable by current GWAS arrays. Resequencing technology and new-generation arrays may help identify these low-frequency variants; larger sample sizes may be needed to detect significant signals. The effort can be further strengthened by applying prior biological and epidemiological data to select associations.