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Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-to-iN neuronal model

Thomas R. Ward, Xianglong Zhang, Louis C. Leung, View ORCID ProfileBo Zhou, Kristin Muench, Julien G. Roth, Arineh Khechaduri, Melanie J. Plastini, Carol Charlton, Reenal Pattni, Steve Ho, Marcus Ho, Yiling Huang, Joachim F. Hallmayer, Phillippe Mourrain, Theo D. Palmer, Alexander E. Urban
doi: https://doi.org/10.1101/2020.02.09.940965
Thomas R. Ward
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Xianglong Zhang
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Louis C. Leung
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
3Stanford Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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Bo Zhou
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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  • ORCID record for Bo Zhou
Kristin Muench
4Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
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Julien G. Roth
4Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
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Arineh Khechaduri
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Melanie J. Plastini
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Carol Charlton
4Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
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Reenal Pattni
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Steve Ho
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Marcus Ho
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Yiling Huang
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Joachim F. Hallmayer
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
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Phillippe Mourrain
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
3Stanford Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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Theo D. Palmer
4Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
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Alexander E. Urban
1Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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  • For correspondence: aeurban@stanford.edu
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Abstract

Copy number variants (CNVs), either deletions or duplications, at the 16p11.2 locus in the human genome are known to increase the risk for autism spectrum disorders (ASD), schizophrenia, and for several other developmental conditions. Here, we investigate the global effects on gene expression and DNA methylation using a 16p11.2 CNV patient-derived induced pluripotent stem cell (iPSC) to induced neuron (iN) cell model system. This approach revealed genome-wide and cell-type specific alterations to both gene expression and DNA methylation patterns and also yielded specific leads on genes potentially contributing to some of the known 16p11.2 patient phenotypes. PCSK9 is identified as a possible contributing factor to the symptoms seen in carriers of the 16p11.2 CNVs. The protocadherin (PCDH) gene family is found to have altered DNA methylation patterns in the CNV patient samples. The iPSC lines used for this study are available through a repository as a resource for research into the molecular etiology of the clinical phenotypes of 16p11.2 CNVs and into that of neuropsychiatric and neurodevelopmental disorders in general.

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Posted February 10, 2020.
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Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-to-iN neuronal model
Thomas R. Ward, Xianglong Zhang, Louis C. Leung, Bo Zhou, Kristin Muench, Julien G. Roth, Arineh Khechaduri, Melanie J. Plastini, Carol Charlton, Reenal Pattni, Steve Ho, Marcus Ho, Yiling Huang, Joachim F. Hallmayer, Phillippe Mourrain, Theo D. Palmer, Alexander E. Urban
bioRxiv 2020.02.09.940965; doi: https://doi.org/10.1101/2020.02.09.940965
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Genome-wide molecular effects of the neuropsychiatric 16p11 CNVs in an iPSC-to-iN neuronal model
Thomas R. Ward, Xianglong Zhang, Louis C. Leung, Bo Zhou, Kristin Muench, Julien G. Roth, Arineh Khechaduri, Melanie J. Plastini, Carol Charlton, Reenal Pattni, Steve Ho, Marcus Ho, Yiling Huang, Joachim F. Hallmayer, Phillippe Mourrain, Theo D. Palmer, Alexander E. Urban
bioRxiv 2020.02.09.940965; doi: https://doi.org/10.1101/2020.02.09.940965

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