@article{b7550108e32e4b4c94fc776ec85707dc,
title = "Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants",
abstract = "Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)-derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.",
author = "Siwei Zhang and Hanwen Zhang and Yifan Zhou and Min Qiao and Siming Zhao and Alena Kozlova and Jianxin Shi and Sanders, {Alan R.} and Gao Wang and Kaixuan Luo and Subhajit Sengupta and Siobhan West and Sheng Qian and Michael Streit and Dimitrios Avramopoulos and Cowan, {Chad A.} and Mengjie Chen and Pang, {Zhiping P.} and Gejman, {Pablo V.} and Xin He and Jubao Duan",
note = "Funding Information: We thank W. J. Greenleaf for helping on ATAC-seq and Rutgers University Cell and DNA Repository (RUCDR; 2U24MH068457) for producing iPSC lines. Funding: Funding was provided by NIH grants R01AA023797 (to Z.P.P.); R01MH113215 (to D.A.); R01MH110531 (to X.H.); and R01MH106575, R01MH116281, and R01AG063175 (to J.D.). Author contributions: S.Zhang analyzed the ATAC-seq, bulk and single-cell RNA sequencing data, CROP-seq, and wrote the manuscript. S.Zhang and H.Z. performed the experiments, analyzed the data, and wrote the manuscript. Y.Z., M.Q., S.Zhao, G.W., K.L., and S.Q. performed computational analyses of tissue-specific ASoC, TF footprints, GWAS enrichment, fine-mapping, and CROP-seq. A.K. and M.S. carried out dopaminergic neuron differentiation. J.S. and S.S. helped with data quality control and statistical analyses. S.W. helped with CROP-seq gRNA design and library preparation. A.R.S. and P.V.G. helped with clinical phenotypes, data interpretation, and manuscript writing. C.A.C. and Z.P.P. guided the gene editing and neuron differentiation, respectively. Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",
year = "2020",
month = jul,
day = "31",
doi = "10.1126/science.aay3983",
language = "English (US)",
volume = "369",
pages = "561--565",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6503",
}