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

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
02 Mar 2023
Historique:
pubmed: 24 4 2023
medline: 24 4 2023
entrez: 24 04 2023
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1101/2023.03.02.530826 PMID: 37090548 PMC: PMC10120699
pubmed: 37090548
doi: 10.1101/2023.03.02.530826
pmc: PMC10120699
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NIMH NIH HHS
ID : RF1 MH128970
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109897
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG050986
Pays : United States
Organisme : NIDA NIH HHS
ID : 75N95019C00049
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067025
Pays : United States
Organisme : BLRD VA
ID : I01 BX002395
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC MH002903
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG065582
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH116438
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH116442
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH125246
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110921
Pays : United States

Déclaration de conflit d'intérêts

Competing interests N.A. is the cofounder and on the scientific advisory board of Regel Therapeutics and receives funding from BioMarin Pharmaceutical Incorporated.

Références

Nat Genet. 2022 Apr;54(4):412-436
pubmed: 35379992
Cell. 2011 Feb 4;144(3):327-39
pubmed: 21295696
Nat Genet. 2022 Aug;54(8):1145-1154
pubmed: 35931864
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Nat Neurosci. 2022 Oct;25(10):1366-1378
pubmed: 36171428
Science. 2022 Mar 18;375(6586):1247-1254
pubmed: 35298243
Genome Res. 2018 Aug;28(8):1243-1252
pubmed: 29945882
Nat Genet. 2015 Nov;47(11):1228-35
pubmed: 26414678
Nat Genet. 2020 Nov;52(11):1158-1168
pubmed: 33106633
Nat Neurosci. 2020 Jun;23(6):771-781
pubmed: 32341540
Science. 2019 Jan 18;363(6424):
pubmed: 30545847
Nat Commun. 2020 Nov 4;11(1):5581
pubmed: 33149216
Nat Genet. 2021 Jun;53(6):817-829
pubmed: 34002096
Science. 2019 May 3;364(6439):
pubmed: 31048460
Nat Commun. 2018 Aug 7;9(1):3121
pubmed: 30087329
Physiol Rep. 2020 May;8(9):e14428
pubmed: 32358861
Am J Hum Genet. 2020 Feb 6;106(2):170-187
pubmed: 32004450
Science. 2022 Aug 19;377(6608):eabi8654
pubmed: 35981026
Nat Genet. 2017 Oct;49(10):1517-1521
pubmed: 28805827
Nat Genet. 2022 Oct;54(10):1493-1503
pubmed: 36163279
Nat Rev Genet. 2018 Aug;19(8):491-504
pubmed: 29844615
Nature. 2022 Apr;604(7906):502-508
pubmed: 35396580
J Neurosci. 2010 Oct 6;30(40):13441-53
pubmed: 20926670
Nat Genet. 2022 Feb;54(2):161-169
pubmed: 35058635
Nat Commun. 2018 Aug 6;9(1):3078
pubmed: 30082721
Nat Commun. 2021 Mar 3;12(1):1424
pubmed: 33658504
Nat Neurosci. 2021 Jul;24(7):941-953
pubmed: 34017130
Biol Psychiatry. 2023 Jul 14;:
pubmed: 37454787
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Nat Protoc. 2020 Aug;15(8):2387-2412
pubmed: 32641802
Nat Neurosci. 2019 Mar;22(3):343-352
pubmed: 30718901
Nat Genet. 2019 Jan;51(1):187-195
pubmed: 30478440
Nat Genet. 2016 Feb;48(2):206-13
pubmed: 26656845
Nat Neurosci. 2022 Aug;25(8):1104-1112
pubmed: 35915177
Genome Biol. 2019 Sep 2;20(1):183
pubmed: 31477158
Nature. 2021 May;593(7858):238-243
pubmed: 33828297
Am J Hum Genet. 2016 Dec 1;99(6):1245-1260
pubmed: 27866706
Science. 2019 Nov 29;366(6469):1134-1139
pubmed: 31727856

Auteurs

Biao Zeng (B)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Jaroslav Bendl (J)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Chengyu Deng (C)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94158, USA.

Donghoon Lee (D)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ruth Misir (R)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Sarah M Reach (SM)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Steven P Kleopoulos (SP)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Pavan Auluck (P)

Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA.

Stefano Marenco (S)

Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA.

David A Lewis (DA)

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

Vahram Haroutunian (V)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY, USA.

Nadav Ahituv (N)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94158, USA.

John F Fullard (JF)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Gabriel E Hoffman (GE)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Panos Roussos (P)

Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY, USA.

Classifications MeSH