Whilst the majority of genetic diseases are due to a small contribution from a large number of genes, such polygenic disorders are inherently more difficult to study than monogenic diseases, since typically both the penetrance and severity of the phenotype due to any single mutation are lower (Wheeler et al. 2016). This is true of any disease model, and our ability to obtain iPSCs from patients with and without a disease makes analysis of polygenic disorders such as autism (DeRosa et al. 2012) or schizophrenia (Brennand et al. 2011) more feasible. However, further genetic manipulations to prove the causal alleles (see below) become more challenging due to the larger number of genes involved, smaller phenotypic effects and the potential for epistasis between different alleles. As with most current models of such diseases, it is often simpler to study the effect of a familial form with higher penetrance and severity, to identify phenotypes that can then be recapitulated in other forms of the disease.
