Abstract:
:Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized ∼100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Forrest MP,Zhang H,Moy W,McGowan H,Leites C,Dionisio LE,Xu Z,Shi J,Sanders AR,Greenleaf WJ,Cowan CA,Pang ZP,Gejman PV,Penzes P,Duan Jdoi
10.1016/j.stem.2017.07.008subject
Has Abstractpub_date
2017-09-07 00:00:00pages
305-318.e8issue
3eissn
1934-5909issn
1875-9777pii
S1934-5909(17)30287-4journal_volume
21pub_type
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