Schizophrenia (SZ) is a common and debilitating neurodevelopmental disorder that affects nearly three million Americans. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Genome wide association studies (GWAS) indicate that SZ risk reflects both highly penetrant rare copy number variants as well as common single nucleotide polymorphisms with small effect sizes. By overlapping GWAS and post-mortem expression analyses, common variants with expression quantitative trait loci (eQTL) that may contribute to altered gene expression and liability in SZ have been identified; however, demonstrating which risk loci are the causal contributors to disease risk remains an intractable problem. Consequently, we propose to apply a human induced pluripotent stem cell (hiPSC)-based approach to manipulate the genotype and/or expression levels of putative causal SZ risk variants, focusing largely on genes implicated in synaptic formation, maturation and function. Through isogenic comparisons, we propose to examine the molecular and functional effects of perturbing five putative causal eQTLs and ten SZ GWAS- associated genes, testing the impact on cis-gene expression, global network expression patterns and synaptic function. Our hope is that this work may identify novel therapeutic points of intervention in order to improve the disease course in individuals with SZ.
The causal role of schizophrenia risk variants in human neurons and astrocytes is unresolved. By combining CRISPR-genetic engineering and human induced pluripotent stem cell models, we propose to test the molecular and functional impact of perturbing the genotype and expression levels of schizophrenia risk alleles. We hope to find insights into the mechanism of disease initiation and progression in schizophrenia, in order to one day reverse the disrupted molecular pathways that contribute to this debilitating disorder.
| Xu, Miao; Lee, Emily M; Wen, Zhexing et al. (2016) Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 22:1101-1107 |
