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

View ORCID ProfileSiwei Zhang, Hanwen Zhang, Min Qiao, Yifan Zhou, View ORCID ProfileSiming Zhao, Alena Kozlova, Jianxin Shi, View ORCID ProfileAlan R. Sanders, View ORCID ProfileGao Wang, View ORCID ProfileSubhajit Sengupta, Siobhan West, Michael Streit, Chad A. Cowan, Mengjie Chen, View ORCID ProfileZhiping P. Pang, View ORCID ProfilePablo V. Gejman, View ORCID ProfileXin He, View ORCID ProfileJubao Duan
doi: https://doi.org/10.1101/827048
Siwei Zhang
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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  • ORCID record for Siwei Zhang
Hanwen Zhang
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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Min Qiao
Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USADepartment of Human Genetics, University of Chicago, Chicago, IL 60637, USA
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Yifan Zhou
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
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Siming Zhao
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
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Alena Kozlova
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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Jianxin Shi
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA
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Alan R. Sanders
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USADepartment of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA
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Gao Wang
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
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  • ORCID record for Gao Wang
Subhajit Sengupta
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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  • ORCID record for Subhajit Sengupta
Siobhan West
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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Michael Streit
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA
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Chad A. Cowan
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
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Mengjie Chen
Department of Medicine, University of Chicago, Chicago, IL 60637, USA
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Zhiping P. Pang
Department of Neuroscience and Cell Biology and Child Health Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
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Pablo V. Gejman
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USADepartment of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA
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Xin He
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USAGrossman Institute for Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL 60637, USA
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  • For correspondence: xinhe@uchicago.edu jduan@uchicago.edu
Jubao Duan
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USADepartment of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA
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  • For correspondence: xinhe@uchicago.edu jduan@uchicago.edu
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Abstract

Functional interpretation of noncoding disease variants, which likely regulate gene expression, has been challenging. Chromatin accessibility strongly influences gene expression during neurodevelopment; however, to what extent genetic variants can alter chromatin accessibility in the context of brain disorders/traits is unknown. Using human induced pluripotent stem cell (iPSC)-derived neurons as a neurodevelopmental model, we identified abundant open-chromatin regions absent in adult brain samples and thousands of genetic variants exhibiting allele-specific open-chromatin (ASoC). ASoC variants are overrepresented in brain enhancers, transcription-factor-binding sites, and quantitative-trait-loci associated with gene expression, histone modification, and DNA methylation. Notably, compared to open chromatin regions and other commonly used functional annotations, neuronal ASoC variants showed much stronger enrichments of risk variants for various brain disorders/traits. Our study provides the first snapshot of the neuronal ASoC landscape and a powerful framework for prioritizing functional disease variants.

One Sentence Summary Allele-specific open chromatin informs functional disease variants

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Posted November 01, 2019.
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Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants
Siwei Zhang, Hanwen Zhang, Min Qiao, Yifan Zhou, Siming Zhao, Alena Kozlova, Jianxin Shi, Alan R. Sanders, Gao Wang, Subhajit Sengupta, Siobhan West, Michael Streit, Chad A. Cowan, Mengjie Chen, Zhiping P. Pang, Pablo V. Gejman, Xin He, Jubao Duan
bioRxiv 827048; doi: https://doi.org/10.1101/827048
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Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants
Siwei Zhang, Hanwen Zhang, Min Qiao, Yifan Zhou, Siming Zhao, Alena Kozlova, Jianxin Shi, Alan R. Sanders, Gao Wang, Subhajit Sengupta, Siobhan West, Michael Streit, Chad A. Cowan, Mengjie Chen, Zhiping P. Pang, Pablo V. Gejman, Xin He, Jubao Duan
bioRxiv 827048; doi: https://doi.org/10.1101/827048

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