Genetic regulation of cell-type specific chromatin accessibility shapes the etiology of brain diseases

Biao Zeng; Jaroslav Bendl; Chengyu Deng; Donghoon Lee; Ruth Misir; Sarah M Reach; Steven P Kleopoulos; Pavan Auluck; Stefano Marenco; David A Lewis; Vahram Haroutunian; Nadav Ahituv; John F Fullard; Gabriel E Hoffman; Panos Roussos

doi:10.1101/2023.03.02.530826

Genetic regulation of cell-type specific chromatin accessibility shapes the etiology of brain diseases

bioRxiv [Preprint]. 2023 Mar 2:2023.03.02.530826. doi: 10.1101/2023.03.02.530826.

Authors

Biao Zeng^{1

2

3

4}, Jaroslav Bendl^{1

2

3

4}, Chengyu Deng^{5

6}, Donghoon Lee^{1

2

3

4}, Ruth Misir^{1

2

3

4}, Sarah M Reach^{1

2

3

4}, Steven P Kleopoulos^{1

2

3

4}, Pavan Auluck⁷, Stefano Marenco⁷, David A Lewis⁸, Vahram Haroutunian^{2

4

9

10}, Nadav Ahituv^{5

6}, John F Fullard^{1

2

3

4}, Gabriel E Hoffman^{1

2

3

4}, Panos Roussos^{1

2

3

4

10}

Affiliations

¹ Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁶ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁷ Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA.
⁸ Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY, USA.

Abstract

Nucleotide variants in cell type-specific gene regulatory elements in the human brain are major risk factors of human disease. We measured chromatin accessibility in sorted neurons and glia from 1,932 samples of human postmortem brain and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTL). Only 10.4% of caQTL are shared between neurons and glia, supporting the cell type specificity of genetic regulation of the brain regulome. Incorporating allele specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms underlying disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs, identifying the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides novel insights into brain disease etiology.

Publication types

Preprint

Abstract

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