Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

Zhang, Siwei; Zhang, Hanwen; Qiao, Min; Zhou, Yifan; Zhao, Siming; Kozlova, Alena; Shi, Jianxin; Sanders, Alan R.; Wang, Gao; Sengupta, Subhajit; West, Siobhan; Streit, Michael; Cowan, Chad A.; Chen, Mengjie; Pang, Zhiping P.; Gejman, Pablo V.; He, Xin; Duan, Jubao

doi:10.1101/827048

Cited by 2 publications

(4 citation statements)

References 38 publications

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“…To ensure that the hiPSCs can robustly generate the neural subtypes most commonly linked to SZ (glutamatergic neurons [63], GABAergic neurons [63], dopaminergic neurons [64], and astrocytes [65]), each laboratory independently evaluated neural differentiation and induction using different methodologies already well established at each site [23, 30, 54, 66, 67]. Forebrain NPCs were generated from all 12 lines [68]; immunofluorescence staining of PAX6 and NESTIN exceeded 95% in 10 out of 12 lines, with NPCs from 2 donors showing impurities (low_PRS_1 and low_PRS_4) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To ensure that the hiPSCs can robustly generate the neural subtypes most commonly linked to SZ (glutamatergic neurons 51 , GABAergic neurons 51 , dopaminergic neurons 52 , and astrocytes 53 ), each laboratory independently evaluated neural differentiation and induction using different methodologies already well-established at each site 23,30,[54][55][56] .…”

Section: Demonstration Of Neuronal and Glial Generationmentioning

confidence: 99%

“…Second, we applied dCas9 to re-target the SZ risk SNP rs7148456 associated with allele-specific open chromatin at the BAG5 locus 55 . In two hiPSC lines, we transfected a customized ABEmax vector system 68 to express the gRNA, dCas9 and ABEmax in a single vector.…”

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confidence: 99%

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Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Dobrindt¹,

Zhang²,

Das³

et al. 2020

Complex Psychiatry

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Schizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.

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Section: Resultsmentioning

confidence: 99%

Section: Demonstration Of Neuronal and Glial Generationmentioning

confidence: 99%

See 1 more Smart Citation

Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Dobrindt¹,

Zhang²,

Das³

et al. 2020

Complex Psychiatry

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Demonstration Of Neuronal and Glial Generationmentioning

confidence: 99%

Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia

Rehbach

Zhang

Das

et al. 2020

Preprint

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ABSTRACTSchizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.

show abstract

Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

Cited by 2 publications

References 38 publications

Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia

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