Genetic regulation of cell type–specific chromatin accessibility shapes brain disease etiology-Reference-Cited by-同舟云学术

Genetic regulation of cell type–specific chromatin accessibility shapes brain disease etiology

Published:2024-05-24 Issue:6698 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Zeng Biao¹²³⁴^ORCID,Bendl Jaroslav¹²³⁴^ORCID,Deng Chengyu⁵⁶^ORCID,Lee Donghoon¹²³⁴^ORCID,Misir Ruth¹²³⁴,Reach Sarah M.¹²³⁴^ORCID,Kleopoulos Steven P.¹²³⁴,Auluck Pavan⁷,Marenco Stefano⁷^ORCID,Lewis David A.⁸^ORCID,Haroutunian Vahram²⁴⁹¹⁰^ORCID,Ahituv Nadav⁵⁶^ORCID,Fullard John F.¹²³⁴^ORCID,Hoffman Gabriel E.¹²³⁴^ORCID,Roussos Panos¹²³⁴¹⁰^ORCID

Affiliation:

1. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

4. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, 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 20892, USA.

8. Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

9. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

10. Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY 10468, USA.

Abstract

Nucleotide variants in cell type–specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type–specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adh4265

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