On the face of it, the widely documented additivity of genetic associations is inconsistent either with the dominance of rare variant effects, or the assumption that they interact multiplicatively within individuals to influence disease. However, it turns out that rare variants can easily induce apparently additive effects statistically, because the homozygotes for the tagging variant are twice as likely as the heterozygotes to carry the rare variant. Multiplicative interactions between rare variants cannot be measured in GWAS because of low power, but it will be important to establish mechanistically whether combinations of two or more such mutations increase risk in a linear or synergistic manner58,59. Compound heterozygosity for two different rare variants at one locus is well documented in diseases such as cystic fibrosis, hemochromatosis and sickle cell syndromes; extension of the concept to include intergenic multiple heterozygosity could represent a large source of genetic variance that is almost impossible to detect with current methods.
