As the “missing heritability” issue emerged in each field, researchers suspected that much of the missing heritability is attributable to genetic variants that are too rare to be detected by GWAS but may have relatively large effects on risk and thus are important to study using next-generation sequencing technologies.131 Both population genetic theories and empirical studies of several complex traits suggest that rare alleles are enriched for functional and deleterious effects and thus are disproportionately represented among disease alleles.132
