Mendelian diseases as quantitative traits

I recently gave a talk at the annual American Society of Human Genetics meeting in the Novel Genes, Novel Regulators, and Monogenic Diseases session. I was very pleased by the reception of my talk and of the main message I was trying to convey. I thought I would briefly rehash the main point: Mendelian diseases are not simple and should be viewed as quantitative traits.

I presented our work on identifying genetic modifiers of Retinitis Pigementosa (RP), a heritable form of retinal degeneration. We crossed a Drosophila model of RP onto ~200 wild-derived Drosophila strains. These strains contain genetic variation found in a wild population and were NOT mutagenized. When on different backgrounds, this Mendelian disease presented with a HUGE range of retinal degeneration. In short, the phenotype was quantitative. We went on to identify a list of novel candidate genes that make a lot of biological sense. We used natural genetic variation to show that this Mendelian disease is, in fact, complex.

This message may be obvious. After all, the push behind precision medicine is the fact that every individual is different and may present with slightly different disease outcomes and respond differently to therapies. However, when speaking to other scientists studying Mendelian diseases, genetic background and modifier genes are a pesky nuisance. I challenge everyone to embrace these effects.

In order to fully understand the phenotypic spectrum and genetic architecture of Mendelian diseases, we need to treat them as quantitative traits.