Schizophrenia（SZ） is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies（GWASs） of SZ have identified 〉100 risk loci. However,the causal variants/genes and the ca...Schizophrenia（SZ） is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies（GWASs） of SZ have identified 〉100 risk loci. However,the causal variants/genes and the causal mechanisms remain largely unknown,which hinders the translation of GWAS fi ndings into disease biology and drug targets. Most risk variants are noncoding,thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling,and open chromatin is a versatile predictor of regulatory sequences. Micro RNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specifi c induced pluripotent stem cells（i PSCs） provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specifi c to cell type and/or developmental stage. The emerging genome-editing technology enables the creation ofisogenic i PSCs and neurons to effi ciently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic,glutamatergic,and GABAergic neurotransmissions. SZ GWAS fi ndings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.展开更多
基金supported by National Institutes of Health (NIH) Grant R21MH102685the North Shore University Health System 2011 Pilot Award
文摘Schizophrenia（SZ） is a devastating mental disorder afflicting 1% of the population. Recent genome-wide association studies（GWASs） of SZ have identified 〉100 risk loci. However,the causal variants/genes and the causal mechanisms remain largely unknown,which hinders the translation of GWAS fi ndings into disease biology and drug targets. Most risk variants are noncoding,thus likely regulate gene expression. A major mechanism of transcriptional regulation is chromatin remodeling,and open chromatin is a versatile predictor of regulatory sequences. Micro RNA-mediated post-transcriptional regulation plays an important role in SZ pathogenesis. Neurons differentiated from patient-specifi c induced pluripotent stem cells（i PSCs） provide an experimental model to characterize the genetic perturbation of regulatory variants that are often specifi c to cell type and/or developmental stage. The emerging genome-editing technology enables the creation ofisogenic i PSCs and neurons to effi ciently characterize the effects of SZ-associated regulatory variants on SZ-relevant molecular and cellular phenotypes involving dopaminergic,glutamatergic,and GABAergic neurotransmissions. SZ GWAS fi ndings equipped with the emerging functional genomics approaches provide an unprecedented opportunity for understanding new disease biology and identifying novel drug targets.
