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The three-dimensional landscape of chromatin accessibility in Alzheimer’s disease

Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar, Eunju Im, James M. Vicari, Samir Rahman, Pengfei Dong, Ruth Misir, Steven P. Kleopoulos, Sarah M. Reach, Pasha Apontes, Biao Zeng, Wen Zhang, Georgios Voloudakis, Ralph A. Nixon, Vahram Haroutunian, Gabriel E. Hoffman, John F. Fullard, Panos Roussos
doi: https://doi.org/10.1101/2021.01.11.426303
Jaroslav Bendl
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Mads E. Hauberg
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
7Department of Biomedicine, Aarhus University, Aarhus, 8000, Denmark
8The Lundbeck Foundation Initiative of Integrative Psychiatric Research (iPSYCH), Aarhus University, Aarhus, 8000, Denmark
9Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, 8000, Denmark
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Kiran Girdhar
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Eunju Im
10Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
11Department of Psychiatry, New York University Langone Health, New York, NY 10016, USA
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James M. Vicari
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Samir Rahman
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Pengfei Dong
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Ruth Misir
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Steven P. Kleopoulos
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Sarah M. Reach
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Pasha Apontes
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Biao Zeng
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Wen Zhang
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Georgios Voloudakis
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Ralph A. Nixon
10Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
11Department of Psychiatry, New York University Langone Health, New York, NY 10016, USA
12Department of Cell Biology, New York University Langone Health, New York, NY 10016, USA
13New York University Neuroscience Institute, New York, NY 10003, USA
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Vahram Haroutunian
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
6Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
14Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, 10468, USA
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Gabriel E. Hoffman
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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John F. Fullard
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Panos Roussos
1Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
10Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
14Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, 10468, USA
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  • For correspondence: panagiotis.roussos@mssm.edu
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Abstract

Much is still unknown about the neurobiology of Alzheimer’s disease (AD). To better understand AD, we generated 636 ATAC-seq libraries from cases and controls to construct detailed genomewide chromatin accessibility maps of neurons and non-neurons from two AD-affected brain regions, the entorhinal cortex and superior temporal gyrus. By analyzing a total of 19.6 billion read pairs, we expanded the known repertoire of regulatory sequences in the human brain. Multi-omic data integration associated global patterns of chromatin accessibility with gene expression and identified cell-specific enhancer-promoter interactions. Using inter-individual variation in chromatin accessibility, we define cis-regulatory domains capturing the 3D structure of the genome. Multifaceted analyses uncovered disease associated perturbations impacting chromatin accessibility, transcription factor regulatory networks and the 3D genome, and implicated transcriptional dysregulation in AD. Overall, we applied a systematic approach to understand the role of the 3D genome in AD and to illuminate novel disease biology that can advance diagnosis and therapy.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 12, 2021.
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The three-dimensional landscape of chromatin accessibility in Alzheimer’s disease
Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar, Eunju Im, James M. Vicari, Samir Rahman, Pengfei Dong, Ruth Misir, Steven P. Kleopoulos, Sarah M. Reach, Pasha Apontes, Biao Zeng, Wen Zhang, Georgios Voloudakis, Ralph A. Nixon, Vahram Haroutunian, Gabriel E. Hoffman, John F. Fullard, Panos Roussos
bioRxiv 2021.01.11.426303; doi: https://doi.org/10.1101/2021.01.11.426303
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The three-dimensional landscape of chromatin accessibility in Alzheimer’s disease
Jaroslav Bendl, Mads E. Hauberg, Kiran Girdhar, Eunju Im, James M. Vicari, Samir Rahman, Pengfei Dong, Ruth Misir, Steven P. Kleopoulos, Sarah M. Reach, Pasha Apontes, Biao Zeng, Wen Zhang, Georgios Voloudakis, Ralph A. Nixon, Vahram Haroutunian, Gabriel E. Hoffman, John F. Fullard, Panos Roussos
bioRxiv 2021.01.11.426303; doi: https://doi.org/10.1101/2021.01.11.426303

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