PT  - JOURNAL ARTICLE
AU  - Gabriel E. Hoffman
AU  - Brigham J. Hartley
AU  - Erin Flaherty
AU  - Ian Ladran
AU  - Peter Gochman
AU  - Doug Ruderfer
AU  - Eli A. Stahl
AU  - Judith Rapoport
AU  - Pamela Sklar
AU  - Kristen J. Brennand
TI  - Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with signatures from post mortem adult brains
AID  - 10.1101/185546
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 185546
4099  - http://biorxiv.org/content/early/2017/09/07/185546.short
4100  - http://biorxiv.org/content/early/2017/09/07/185546.full
AB  - Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. In developing a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons, we identified and accounted for a variety of technical and biological sources of variation. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal in hiPSC-based models and increased the concordance with post mortem datasets. Because this concordance was strongest in hiPSC-neurons, it suggests that this cell type may better model genetic risk for SZ. We predict a growing convergence between hiPSC and post mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.