Complex traits and diseases, such as body-mass index, height, diabetes, heart disease, and psychiatric disorders are undoubtedly caused by multiple genetic and environmental factors, although it has been a major challenge to identify specific genes. Recently, genome-wide association studies (GWAS) have resulted in the detection of many robustly associated single nucleotide polymorphism (SNP) variants across a range of outcomes [1], although for any particular disease or trait the SNP variants detected explain only a fraction of the total genetic variance calculated from family studies. The gap between the two has been termed the “missing heritability” [2],[3]. Many reasons for the missing heritability have been given [3]. One plausible explanation is that rare variants, which existing GWAS platforms are not designed to capture, make significant contributions to the heritability of many traits and diseases. It is indeed likely that many multifactorial and heterogeneous phenotypes will be influenced by a diverse array of genetic factors that span the spectrum from private mutation to common variant. Dickson and colleagues [4],[5] recently took a step further, by arguing that rare variants might explain not
