Evaluation of chromatin accessibility in prefrontal cortex of schizophrenia cases and controls

Bryois, Julien; Garrett, Melanie E; Song, Lingyun; Safi, Alexias; Giusti-Rodriguez, Paola; Johnson, Graham D; Demur, Alfonso Buil; Fullard, John F; Roussos, Panos; Sklar, Pamela; Akbarian, Schahram; Haroutunian, Vahram; Stockmeier, Craig A; Wray, Gregory A; White, Kevin P; Liu, Chunyu; Reddy, Timothy E; Ashley-Koch, Allison; Sullivan, Patrick F; Crawford, Gregory E

doi:10.1101/141986

PreprintCited by 7Schizophrenia research and treatmentGenomics and Chromatin DynamicsGenetic Associations and Epidemiology

Evaluation of chromatin accessibility in prefrontal cortex of schizophrenia cases and controls

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Bryois, Julien, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Giusti-Rodriguez, Paola, Johnson, Graham D, Demur, Alfonso Buil, Fullard, John F +12 more·2017·bioRxiv (Cold Spring Harbor Laboratory)

DOI 10.1101/141986

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Abstract

Abstract Schizophrenia genome-wide association (GWA) studies have identified over 150 regions of the genome that are associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in brain are highly enriched for SNP-heritability for schizophrenia (10.6 fold enrichment, P=2.4×10 −4 , second only to genomic regions conserved in Eutherian mammals) and replicated in an independent dataset (9.0 fold enrichment, P=2.7×10 −4 ). This degree of enrichment of schizophrenia heritability was higher than in open chromatin found in 138 different cell and tissue types. Brain open chromatin regions that overlapped highly conserved regions exhibited an even higher degree of heritability enrichment, indicating that conservation can identify functional subsets within regulatory elements active in brain. However, we did not identify chromatin accessibility differences between schizophrenia cases and controls, nor did we find an interaction of chromatin QTLs with case-control status. This indicates that although causal variants map within regulatory elements, mechanisms other than differential chromatin may govern the contribution of regulatory element variation to schizophrenia risk. Our results strongly implicate gene regulatory processes involving open chromatin in the pathogenesis of schizophrenia, and suggest a strategy to understand the hundreds of common variants emerging from large genomic studies of complex brain diseases.

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Authors: Bryois, J., Garrett, M. E., Song, L., Safi, A., Giusti-Rodriguez, P., Johnson, G. D., Demur, A. B., Fullard, J. F., Roussos, P., Sklar, P., Akbarian, S., Haroutunian, V., Stockmeier, C. A., Wray, G. A., White, K. P., Liu, C., Reddy, T. E., Ashley-Koch, A., Sullivan, P. F., & Crawford, G. E.
Affiliations: Karolinska Institutet (SE)
Duke University (US)
Sankt Hans Hospital (DK)
Icahn School of Medicine at Mount Sinai (US)
James J. Peters VA Medical Center (US)
University of Mississippi Medical Center (US)
University of Chicago (US)
University of Illinois Chicago (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Sullivan, Patrick F
Crawford, Gregory E
ORCID: Bryois, Julien
Song, Lingyun
Safi, Alexias
Johnson, Graham D
Fullard, John F
Roussos, Panos
Sklar, Pamela
Akbarian, Schahram
Haroutunian, Vahram
Stockmeier, Craig A
Wray, Gregory A
White, Kevin P
Liu, Chunyu
Reddy, Timothy E
Sullivan, Patrick F
Crawford, Gregory E
Venue: bioRxiv (Cold Spring Harbor Laboratory)
Publisher: openRxiv
Published: 2017-05-25
DOI: 10.1101/141986
OpenAlex: W2618778878
Cited by: 7
References: 110
Citations by year: 2025: 1 · 2020: 1 · 2019: 1 · 2018: 4
Type: posted content
Language: en
Open access: green
doi.org
Licence: www.biorxiv.org/about/FAQ#license (vor)
Locations: bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: schizophrenia, chromatin accessibility, prefrontal cortex, open chromatin, non-coding regulatory elements, heritability, SNP heritability, evolutionary conservation, gene expression regulation

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Evaluation of chromatin accessibility in prefrontal cortex of schizophrenia cases and controls

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