The broad-sense heritability model posits that additive contributions of common variants and large effects of rare variants are insufficient to explain the missing heritability. Proponents of this model point to a long history of detection of genotype-by-genotype interactions (epistasis) and genotype-by-environment interactions (G×E) in model organism quantitative genetic research20,21, and note the increasing number of studies documenting epigenetic effects22, notably parent-of-origin genetic contributions23,24 and inheritance of DNA methylation patterns25. The notion here is that since GWAS only measure the average effects of alleles across thousands of individuals, they are incapable of capturing heterogeneity of effect sizes at the family level that would be the hallmark of these broader components of the genetic architecture. Although broad-sense heritability is not considered further in this article (but see Box 1), I do not disregard its potential contribution. Rather, my purpose here is to contrast the two narrow sense models, as resolution of their contributions lays the foundation for consideration of other genetic mechanisms.
