Abstract

BackgroundSchizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. 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.MethodsWe reprogrammed fibroblasts from SZ patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into neural progenitor cells (NPCs) and neurons. Our hiPSC neural cells, from controls and patients with SZ, better resemble fetal rather than adult brain tissue, indicating that hiPSC-based models may be best suited for studies of disease predisposition. At the cellular level, we have previously reported aberrant migration in SZ hiPSC NPCs, together with diminished neuronal connectivity and impaired synaptic function in SZ hiPSC neurons.ResultsWe identified microRNA-9 as having significantly downregulated levels and activity in a subset of SZ hiPSC-derived neural progenitor cells NPCs, a finding that was corroborated by a larger replication cohort and further validated by an independent gene-set enrichment analysis of the largest SZ genome-wide association study (GWAS) to date. Overall, this demonstrated a remarkable convergence of independent hiPSC- and genetics-based discovery approaches. In developing this larger case/control SZ hiPSC cohort of hiPSC-derived NPCs and neurons, we identified a variety of sources of variation, but by reducing the stochastic effects of the differentiation process, we observed a significant concordance with two large post mortem datasets.DiscussionWe predict a growing convergence between hiPSC and post mortem studies as both approaches expand to larger cohort sizes. Meanwhile, we have been integrating CRISPR-mediated gene editing, activation and repression technologies with our hiPSC-based neural platform, in order to develop a scalable system for testing the effect of a manipulating the growing number of SZ-associated variants and genes in NPCs, neurons and astrocytes. Altogether, our objective is to understand the cell-type specific contributions of SZ risk variants to disease predisposition.

Highlights

  • Neuropsychiatric disorders, including schizophrenia (SZ), afflict a significant fraction of the population

  • At a leading SZ-risk locus flanking MIR137, we further examined the functional effects of a prioritized common genome-wide association studies (GWAS) SNP rs1198588 in CRISPR/Cas9-edited human induced pluripotent stem cell (hiPSC), and found that SZ-risk allele of rs1198588 altered MIR137 expression, open chromatin regions (OCRs) dynamics and dendrite arborization/ synapse maturation

  • Out of the 12 schizophrenia GWAS-implicated SNPs that we found in neuronal OCRs of this single individual, two SNPs showed allele-specific open chromatin (ASoC) and are putatively functional: one lies within the 5’-UTR of CHRNA5 and the other is in the promoter region of VPS45, a Sec1 family gene involved in synaptic transmission

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Summary

Background

Schizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. Results: We identified microRNA-9 as having significantly downregulated levels and activity in a subset of SZ hiPSC-derived neural progenitor cells NPCs, a finding that was corroborated by a larger replication cohort and further validated by an independent gene-set enrichment analysis of the largest SZ genome-wide association study (GWAS) to date. Overall, this demonstrated a remarkable convergence of independent hiPSC- and genetics-based discovery approaches. Our objective is to understand the cell-type specific contributions of SZ risk variants to disease predisposition

Overall Abstract
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