Focusing exclusively on exome is an especially serious limitation in complex trait genetics, where noncoding genetic variation is believed to play a larger role than in Mendelian genetics or in somatic cancer genetics. However, there are clear reasons to start with exomes. First, statistical approaches combining multiple rare variants are problematic in non-coding regions because there is no easily identifiable set of sites harboring variants with unidirectional phenotypic effects. Second, variants in regulatory regions are likely to have smaller effect sizes. In contrast, protein coding genes provide a well-defined and interpretable target for mutations in the locus. These mutations create variants that, in a well-powered study, highlight association of the locus with the trait. Thus, although focusing on the exome is unlikely to explain all of heritability, it has the potential to highlight genes involved in complex traits.
