Cell type-specific epigenetic links to schizophrenia risk in the brain

• Type of Material: Article
• Authors: Isabel Mendizabal, Georgia Institute of Technology; Stefano Berto, University of Texas Southwestern Medical Center; Noriyoshi Usui, University of Texas Southwestern Medical Center; Kazuya Toriumi, University of Texas Southwestern Medical Center; Paramita Chatterjee, Georgia Institute of Technology; Connor Douglas, University of Texas Southwestern Medical Center; Iksoo Huh, Georgia Institute of Technology; Hyeonsoo Jeong, Georgia Institute of Technology; Thomas Layman, Georgia Institute of Technology; Carol A. Tamminga, University of Texas Southwestern Medical Center; Todd M Preuss, Emory University; Genevieve Konopka, University of Texas Southwestern Medical Center; Soojin V. Yi, Georgia Institute of Technology
• Language: English
• Date: 2019-07-09
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-019-1747-7
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1474-7596
• Volume: 20
• Issue: 1
• Start Page: 135
• End Page: 135
• Grant/Funding Information: This work was supported by the Uehara Memorial Foundation to NU; JSPS Grant-in-Aid for Early-Career Scientists (18 K14814) to NU; Scientific Research (C) (18K06977) to KT; Takeda Science Foundation to NU; the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2603) to SB, NU, KT, and GK; the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition – Scholar Award to GK; National Science Foundation (SBE-131719) to SVY; the National Chimpanzee Brain Resource, NIH R24NS092988, the NIH National Center for Research Resources P51RR165 (superseded by the Office of Research Infrastructure Programs/OD P51OD11132) to TMP; and the NIMH (MH103517) to TMP, GK, and SVY.; Human tissue samples were obtained from the NIH NeuroBioBank (The Harvard Brain Tissue Resource Center, funded through HHSN-271-2013-00030C; the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center; and the University of Miami Brain Endowment Bank); and the UT Psychiatry Psychosis Research Program (Dallas Brain Collection).; GK is a Jon Heighten Scholar in Autism Research at UT Southwestern.
• Keywords: NEURONAL NUCLEAR ANTIGEN; Biotechnology & Applied Microbiology; Oligodendrocyte; ENRICHMENT; Neuron; Schizophrenia; GENETIC ARCHITECTURE; DNA METHYLATION; GENOTYPE; Epigenetics; Neurogenomics; DIVERSITY; Life Sciences & Biomedicine; Brain cell type; PACKAGE; WIDE ASSOCIATION; Genetics & Heredity; INSIGHTS; LOCI; Science & Technology; DNA methylation; Transcriptome
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

Abstract

Background: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. Results: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. Conclusions: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.