Common Complex Diseases
The majority of the disease burden that modern societies endure can be attributed to common complex diseases. These diseases typically have both genetic and environmental causes, and they also possess significant genetic heterogeneity, making the identification of disease-causing genes very challenging. Traditionally, the use of linkage analysis of families with extreme disease phenotypes has been somewhat successful in mutation discovery [12]. However, these mutations are particular to patients with extreme phenotypes and do not explain the pathophysiology of disease for patients in the general population. Large genome-wide association studies of common variants have also been employed with limited success; the findings in many studies are not robust and only explain a small fraction of the disease risk [13]. As a result, greater attention has been drawn to profiling rare variants with allele frequencies of less than 1% in complex diseases.
Taking advantage of WES technology, several large-scale projects have been launched. One such example is a project led by National Heart, Lung, and Blood Institute (NHLBI) to discover novel genes underlying cardiovascular disorders. As a result of sequencing the exomes of 2,440 individuals, the study reported an excess of rare functional variants and concluded that large numbers of subjects will be required to attain sufficient power to discover variants that are significantly associated with the disease traits [14].