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Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants

Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J. Armand, Kimberly Siletti, Trygve E. Bakken, Rongxin Fang, Wayne I. Doyle, Rebecca D. Hodge, Lijuan Hu, Bang-An Wang, Zhuzhu Zhang, Sebastian Preissl, Dong-Sung Lee, Jingtian Zhou, Sheng-Yong Niu, Rosa Castanon, Anna Bartlett, Angeline Rivkin, Xinxin Wang, Jacinta Lucero, Joseph R. Nery, David A. Davis, Deborah C. Mash, Jesse R. Dixon, Sten Linnarsson, Ed Lein, M. Margarita Behrens, Bing Ren, Eran A. Mukamel, Joseph R. Ecker
doi: https://doi.org/10.1101/2019.12.11.873398
Chongyuan Luo
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
2Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
3Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA
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  • For correspondence: ecker@salk.edu emukamel@ucsd.edu cluo@mednet.ucla.edu
Hanqing Liu
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
4Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037, USA
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Fangming Xie
5Department of Physics, University of California, San Diego, La Jolla, CA 92037, USA
6Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA
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Ethan J. Armand
6Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA
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Kimberly Siletti
7Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Trygve E. Bakken
8Allen Institute for Brain Science, Seattle, WA, USA
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Rongxin Fang
9Ludwig Institute for Cancer Research, La Jolla, CA, USA
10Center for Epigenomics, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, CA, USA
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Wayne I. Doyle
6Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA
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Rebecca D. Hodge
8Allen Institute for Brain Science, Seattle, WA, USA
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Lijuan Hu
7Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Bang-An Wang
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Zhuzhu Zhang
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Sebastian Preissl
10Center for Epigenomics, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, CA, USA
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Dong-Sung Lee
11Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
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Jingtian Zhou
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Sheng-Yong Niu
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Rosa Castanon
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Anna Bartlett
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Angeline Rivkin
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Xinxin Wang
9Ludwig Institute for Cancer Research, La Jolla, CA, USA
10Center for Epigenomics, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, CA, USA
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Jacinta Lucero
12Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Joseph R. Nery
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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David A. Davis
13Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
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Deborah C. Mash
13Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
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Jesse R. Dixon
11Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA
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Sten Linnarsson
7Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Ed Lein
8Allen Institute for Brain Science, Seattle, WA, USA
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M. Margarita Behrens
12Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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Bing Ren
9Ludwig Institute for Cancer Research, La Jolla, CA, USA
10Center for Epigenomics, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, CA, USA
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Eran A. Mukamel
6Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA
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  • For correspondence: ecker@salk.edu emukamel@ucsd.edu cluo@mednet.ucla.edu
Joseph R. Ecker
1Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
2Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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  • For correspondence: ecker@salk.edu emukamel@ucsd.edu cluo@mednet.ucla.edu
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ABSTRACT

Single-cell technologies enable measure of unique cellular signatures, but are typically limited to a single modality. Computational approaches allow integration of diverse single-cell datasets, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells in tissues, we devised single-nucleus methylCytosine, Chromatin accessibility and Transcriptome sequencing (snmC2T-seq) and applied it to post-mortem human frontal cortex tissue. We developed a computational framework to validate fine-grained cell types using multi-modal information and assessed the effectiveness of computational integration methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling prediction of cell types with causal roles in disease.

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Posted December 12, 2019.
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Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants
Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J. Armand, Kimberly Siletti, Trygve E. Bakken, Rongxin Fang, Wayne I. Doyle, Rebecca D. Hodge, Lijuan Hu, Bang-An Wang, Zhuzhu Zhang, Sebastian Preissl, Dong-Sung Lee, Jingtian Zhou, Sheng-Yong Niu, Rosa Castanon, Anna Bartlett, Angeline Rivkin, Xinxin Wang, Jacinta Lucero, Joseph R. Nery, David A. Davis, Deborah C. Mash, Jesse R. Dixon, Sten Linnarsson, Ed Lein, M. Margarita Behrens, Bing Ren, Eran A. Mukamel, Joseph R. Ecker
bioRxiv 2019.12.11.873398; doi: https://doi.org/10.1101/2019.12.11.873398
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Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants
Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J. Armand, Kimberly Siletti, Trygve E. Bakken, Rongxin Fang, Wayne I. Doyle, Rebecca D. Hodge, Lijuan Hu, Bang-An Wang, Zhuzhu Zhang, Sebastian Preissl, Dong-Sung Lee, Jingtian Zhou, Sheng-Yong Niu, Rosa Castanon, Anna Bartlett, Angeline Rivkin, Xinxin Wang, Jacinta Lucero, Joseph R. Nery, David A. Davis, Deborah C. Mash, Jesse R. Dixon, Sten Linnarsson, Ed Lein, M. Margarita Behrens, Bing Ren, Eran A. Mukamel, Joseph R. Ecker
bioRxiv 2019.12.11.873398; doi: https://doi.org/10.1101/2019.12.11.873398

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