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Evaluation of Chromatin Accessibility in Prefrontal Cortex of Schizophrenia Cases and Controls

Julien Bryois, Melanie E Garrett, Lingyun Song, Alexias Safi, Paola Giusti-Rodriguez, Graham D Johnson, Alfonso Buil Demur, John F Fullard, Panos Roussos, Pamela Sklar, Schahram Akbarian, Vahram Haroutunian, Craig A Stockmeier, Gregory A Wray, Kevin P White, Chunyu Liu, Timothy E Reddy, Allison Ashley-Koch, Patrick F Sullivan, Gregory E Crawford
doi: https://doi.org/10.1101/141986
Julien Bryois
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden
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Melanie E Garrett
Duke Molecular Physiology Institute, Durham, NC, 27701, USA
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Lingyun Song
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA
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Alexias Safi
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA
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Paola Giusti-Rodriguez
Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599-7264, USA
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Graham D Johnson
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA
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Alfonso Buil Demur
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, Denmark
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John F Fullard
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Panos Roussos
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USADepartment Department of Genetics and Genomic Sciences, and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USAMental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, 10468, USA
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Pamela Sklar
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Schahram Akbarian
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Vahram Haroutunian
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Craig A Stockmeier
Center for Psychiatric Neuroscience, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, 39216, USA
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Gregory A Wray
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USADepartment of Biology, Duke University, Durham, NC 27708, USA
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Kevin P White
Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA
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Chunyu Liu
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60607, USA
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Timothy E Reddy
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USADepartment of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, USA
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Allison Ashley-Koch
Duke Molecular Physiology Institute, Durham, NC, 27701, USADepartment of Medicine, Duke University, Durham, NC 27708, USA
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Patrick F Sullivan
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, SwedenDepartment of Genetics, University of North Carolina, Chapel Hill, NC, 27599-7264, USADepartment of Psychiatry, University of North Carolina, Chapel Hill, NC, 27599-7264, USA
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  • For correspondence: greg.crawford@duke.edu pfsulliv@med.unc.edu
Gregory E Crawford
Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USADepartment of Pediatrics, Medical Genetics Division, Duke University, Durham, NC 27708, USA
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  • For correspondence: greg.crawford@duke.edu pfsulliv@med.unc.edu
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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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Posted May 25, 2017.
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Evaluation of Chromatin Accessibility in Prefrontal Cortex of Schizophrenia Cases and Controls
Julien Bryois, Melanie E Garrett, Lingyun Song, Alexias Safi, Paola Giusti-Rodriguez, Graham D Johnson, Alfonso Buil Demur, John F Fullard, Panos Roussos, Pamela Sklar, Schahram Akbarian, Vahram Haroutunian, Craig A Stockmeier, Gregory A Wray, Kevin P White, Chunyu Liu, Timothy E Reddy, Allison Ashley-Koch, Patrick F Sullivan, Gregory E Crawford
bioRxiv 141986; doi: https://doi.org/10.1101/141986
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Evaluation of Chromatin Accessibility in Prefrontal Cortex of Schizophrenia Cases and Controls
Julien Bryois, Melanie E Garrett, Lingyun Song, Alexias Safi, Paola Giusti-Rodriguez, Graham D Johnson, Alfonso Buil Demur, John F Fullard, Panos Roussos, Pamela Sklar, Schahram Akbarian, Vahram Haroutunian, Craig A Stockmeier, Gregory A Wray, Kevin P White, Chunyu Liu, Timothy E Reddy, Allison Ashley-Koch, Patrick F Sullivan, Gregory E Crawford
bioRxiv 141986; doi: https://doi.org/10.1101/141986

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