In this work, we sought to simplify the question of genetic diversity by using genetically related individuals rather than genetically unrelated cases and controls under what we consider a family-based paradigm for iPSC modeling of complex human genetic disorder. To this end, we generated clonally independent iPSCs (rather than clones derived from the same founding cell line), as well as highly purified, expandable, CXCR4+ NPCs from multiple members of the same family with unaffected and BD individuals. This family-based paradigm using a pedigree enriched for neuropsychiatric phenotypes42, has the advantage of controlling for genetic background, and enhancing the chance that both affected individuals share the same underlying BD etiology. In the future, as higher throughput methods for iPSC generation are brought to bear, following such a paradigm will allow the field to carry out more adequately powered studies. Given the density of psychopathology found within the pedigree of Family-811 from which the nuclear family we reprogrammed was derived, a priority for the future should be to reprogram additional family members for which fibroblasts already exist in order determine whether other family members with BD exhibit the same phenotypes relative to other unaffected family members.
