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

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.

SUBMITTER: Mendizabal I

PROVIDER: S-EPMC6617737 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Mendizabal Isabel I Berto Stefano S Usui Noriyoshi N Toriumi Kazuya K Chatterjee Paramita P Douglas Connor C Huh Iksoo I Jeong Hyeonsoo H Layman Thomas T Tamminga Carol A CA Preuss Todd M TM Konopka Genevieve G Yi Soojin V SV

Genome biology 20190709 1

<h4>Background</h4>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.<h4>Results</h4>The methylomes of the two cell types are highly distinct, with th ...[more]

PMID: 31288836

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Project description:ImportanceSchizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is unknown whether these predict established brain alterations associated with schizophrenia.ObjectiveTo identify an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders.Design, setting, and participantsIn this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 [55.5%]) and participants with schizophrenia (803 [36.0%]), bipolar disorder (39 [1.7%]), major depressive disorder 35 [1.6%]), and autism (27 [1.2%]), and first-degree relatives of all patient groups (88 [3.9%]) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019.Main outcomes and measuresThe accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity.ResultsThis study included 7488 participants (4395 men [58.7%]), of whom 3158 (2230 men [70.6%]) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24?×?10-7) and data from postmortem DLPFC samples (AUC?=?0.63; P?=?1.42?×?10-4), but not with major depressive disorder (AUC?=?0.51; P?=?.16), autism (AUC?=?0.53; P?=?.66), or bipolar disorder (AUC?=?0.58; P?=?.21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t?<?-3.81; P for familywise error, <.04; validation magnetic resonance imaging, t?<?-3.54; P for familywise error, <.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P?>?.19).Conclusions and relevanceWe identified a reproducible blood DNA-methylation signature specific for schizophrenia that was correlated with altered functional DLPFC-HC coupling during working memory and mapped to methylation differences found in DLPFC postmortem samples. This indicates a possible epigenetic contribution to a schizophrenia intermediate phenotype and suggests that PMS could be of interest to be studied in the context of multimodal biomarkers for disease stratification and treatment personalization.

Dataset Information

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

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

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