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Cited by 175Epigenetics and DNA MethylationSchizophrenia research and treatmentGenomics and Chromatin Dynamics

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Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia

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Pidsley, Ruth, Viana, Joana, Hannon, Eilis, Spiers, Helen, Troakes, Claire, Al-Saraj, Safa, Mechawar, Naguib, Turecki, Gustavo, Schalkwyk, Leonard C, Bray, Nicholas J, Mill, Jonathan·2014·Genome biology
DOI 10.1186/s13059-014-0483-2PMC PMC4262979
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Abstract

BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances ine arly brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. RESULTS: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci,particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples.Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that schizophrenia-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. CONCLUSIONS: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects.

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Figure 1 Schizophrenia-associated DNA methylation differences in the prefrontal cortex. (A) Probes associated with four genes are significantly associated with schizophrenia at FDR ≤0.05: GSDMD (control = 78.9 ± 3.0, schizophrenia = 83.3 ± 1.3, FDR = 0.03); RASA3 (control = 65.1 ± 4.7, schizophrenia = 56.4 ± 4.1, FDR = 0.03); HTR5A (control = 11.5 ± 1.7, schizophrenia = 9.2 ± 1.2, FDR = 0.03); and PPFIA1 (control = 53.1 ± 3.2, schizophrenia = 47.6 ± 3.2, FDR = 0.03). (B) The top-ranked differentially methylated region is located in an intergenic CpG island in NRN1 where there is coordinated hypomethylation across 29 adjacent CpG sites in schizophrenia patients (red) compared with controls (blue). The mean DNA methylation difference across all 29 sites is -1.77% (FDR = 3.1e-2), with a notable region of hypomethylation (-3.7%) spanning three consecutive DMPs (FDR = 2.4e-2). (C) Selected schizophrenia-associated DMPs were successfully validated and replicated. Shown are technical validation data for the CpG site corresponding to probe cg24803255 in RASA3 confirming significant schizophrenia-associated hypomethylation (control = 70.5 ± 3.7, schizophrenia = 66.4 ± 3.2, P = 0.0002). Additional technical validation data for other loci are shown in Figure S2 in Additional file 1. Also shown are replication data for cg24803255 in RASA3 in PFC from the Montreal cohort confirming significant schizophrenia-associated hypomethylation (control = 65.1 ± 5.5, schizophrenia = 61.3 ± 4.7, P = 0.05). (D) DNA methylation differences at the 100 top-ranked PFC DMPs identified in the London discovery cohort are significantly correlated with schizophrenia-associated differences at the same probes in PFC from the Montreal replication cohort (r = 0.54, P = 6.8e-09).
Figure 1 Schizophrenia-associated DNA methylation differences in the prefrontal cortex. (A) Probes associated with four genes are significantly associated with schizophrenia at FDR ≤0.05: GSDMD (control = 78.9 ± 3.0, schizophrenia = 83.3 ± 1.3, FDR = 0.03); RASA3 (control = 65.1 ± 4.7, schizophrenia = 56.4 ± 4.1, FDR = 0.03); HTR5A (control = 11.5 ± 1.7, schizophrenia = 9.2 ± 1.2, FDR = 0.03); and PPFIA1 (control = 53.1 ± 3.2, schizophrenia = 47.6 ± 3.2, FDR = 0.03). (B) The top-ranked differentially methylated region is located in an intergenic CpG island in NRN1 where there is coordinated hypomethylation across 29 adjacent CpG sites in schizophrenia patients (red) compared with controls (blue). The mean DNA methylation difference across all 29 sites is -1.77% (FDR = 3.1e-2), with a notable region of hypomethylation (-3.7%) spanning three consecutive DMPs (FDR = 2.4e-2). (C) Selected schizophrenia-associated DMPs were successfully validated and replicated. Shown are technical validation data for the CpG site corresponding to probe cg24803255 in RASA3 confirming significant schizophrenia-associated hypomethylation (control = 70.5 ± 3.7, schizophrenia = 66.4 ± 3.2, P = 0.0002). Additional technical validation data for other loci are shown in Figure S2 in Additional file 1. Also shown are replication data for cg24803255 in RASA3 in PFC from the Montreal cohort confirming significant schizophrenia-associated hypomethylation (control = 65.1 ± 5.5, schizophrenia = 61.3 ± 4.7, P = 0.05). (D) DNA methylation differences at the 100 top-ranked PFC DMPs identified in the London discovery cohort are significantly correlated with schizophrenia-associated differences at the same probes in PFC from the Montreal replication cohort (r = 0.54, P = 6.8e-09).CC BY · PubMed Central
Figure 2 Schizophrenia-associated gene co-methylation modules in the prefrontal cortex. (A) Heatmap representing correlations between module eigenvalues (ME) and clinical/demographic variables. Each row represents a specific module, indicated by an arbitrary module color labeled on the y-axis. Dark red indicates strong positive correlation, dark green indicates strong negative correlation, and white indicates no correlation, as indicated in color scale bar. P-values are given in parentheses. The black (P = 0.0004) and pink (P = 0.002) WGCNA modules are most significantly associated with schizophrenia in the PFC. (B) Module membership in both modules is strongly correlated with probe significance with disease (black module: r = 0.39, P <1e-200; pink module: r = 0.22, P = 2.4e-49). (C) Ingenuity Pathway Analysis of genes associated with CpG sites in the black module reveals a highly significant enrichment of disease pathways related to schizophrenia and other neuropsychiatric disease. (D) Co-methylation networks between the top 1% of loci in the black and pink modules ranked by their module membership, where thicker lines indicate more connected genes. Black edges represent co-methylation between probes in the black module and pink edges represent co-methylation in the pink module; thicker and deeper colored edges indicate stronger correlations between probes. Interestingly, the two modules are connected by SHANK2, which encodes a molecular scaffold protein that plays a role in synaptogenesis. Furthermore, several of the genes are associated with schizophrenia in recent collaborative genome-wide association studies (GWAS) [27]. GWAS significance for SNPs in the vicinity of each locus is depicted by color.
Figure 2 Schizophrenia-associated gene co-methylation modules in the prefrontal cortex. (A) Heatmap representing correlations between module eigenvalues (ME) and clinical/demographic variables. Each row represents a specific module, indicated by an arbitrary module color labeled on the y-axis. Dark red indicates strong positive correlation, dark green indicates strong negative correlation, and white indicates no correlation, as indicated in color scale bar. P-values are given in parentheses. The black (P = 0.0004) and pink (P = 0.002) WGCNA modules are most significantly associated with schizophrenia in the PFC. (B) Module membership in both modules is strongly correlated with probe significance with disease (black module: r = 0.39, P <1e-200; pink module: r = 0.22, P = 2.4e-49). (C) Ingenuity Pathway Analysis of genes associated with CpG sites in the black module reveals a highly significant enrichment of disease pathways related to schizophrenia and other neuropsychiatric disease. (D) Co-methylation networks between the top 1% of loci in the black and pink modules ranked by their module membership, where thicker lines indicate more connected genes. Black edges represent co-methylation between probes in the black module and pink edges represent co-methylation in the pink module; thicker and deeper colored edges indicate stronger correlations between probes. Interestingly, the two modules are connected by SHANK2, which encodes a molecular scaffold protein that plays a role in synaptogenesis. Furthermore, several of the genes are associated with schizophrenia in recent collaborative genome-wide association studies (GWAS) [27]. GWAS significance for SNPs in the vicinity of each locus is depicted by color.CC BY · PubMed Central
Figure 3 Schizophrenia associated DMPs are enriched for CpG sites undergoing epigenetic changes during fetal neocortex brain development. (A) Correlation between DNA methylation and neurodevelopmental age (days post-conception) for 98 of the 100 top-ranked schizophrenia-associated DMPs (blue) with corresponding FDR values (red). Dashed lines demarcate DMPs with FDR <0.01. (B) Distribution of the number of CpG sites significantly associated with neocortex brain development (FDR <0.05) using 10,000 permutations of 98 randomly selected CpG sites. The red arrow represents the number of significant (FDR <0.05) age-correlated CpG sites (n = 44) among the 100 top-ranked schizophrenia-associated DMPs. (C,D) A CpG site in MYT1L, for example, significantly hypomethylated in schizophrenia (P = 0.00000175) (C) is highly correlated with neocortical development (FDR = 1.39e-13) (D). Blue points represent male samples and pink points represent female samples.Other examples of schizophrenia-associated DMPs correlated with neocortical development are shown in Figure S6 and Table S13 in Additional file 1.
Figure 3 Schizophrenia associated DMPs are enriched for CpG sites undergoing epigenetic changes during fetal neocortex brain development. (A) Correlation between DNA methylation and neurodevelopmental age (days post-conception) for 98 of the 100 top-ranked schizophrenia-associated DMPs (blue) with corresponding FDR values (red). Dashed lines demarcate DMPs with FDR <0.01. (B) Distribution of the number of CpG sites significantly associated with neocortex brain development (FDR <0.05) using 10,000 permutations of 98 randomly selected CpG sites. The red arrow represents the number of significant (FDR <0.05) age-correlated CpG sites (n = 44) among the 100 top-ranked schizophrenia-associated DMPs. (C,D) A CpG site in MYT1L, for example, significantly hypomethylated in schizophrenia (P = 0.00000175) (C) is highly correlated with neocortical development (FDR = 1.39e-13) (D). Blue points represent male samples and pink points represent female samples.Other examples of schizophrenia-associated DMPs correlated with neocortical development are shown in Figure S6 and Table S13 in Additional file 1.CC BY · PubMed Central

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Authors
Pidsley, R., Viana, J., Hannon, E., Spiers, H., Troakes, C., Al-Saraj, S., Mechawar, N., Turecki, G., Schalkwyk, L. C., Bray, N. J., & Mill, J.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • University of Exeter (GB)
  • King's College London (GB)
  • Douglas Mental Health University Institute (CA)
  • University of Essex (GB)
Corresponding author
Mill, Jonathan
ORCID
Venue
Genome biology
Publisher
Springer Science and Business Media LLC
Published
2014-10-28
Volume
15
Issue
10
Pages
483-483
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/s13059-014-0483-2
PMC
PMC4262979
OpenAlex
W1980511338
Cited by
157
References
40
Citations by year
2026: 2 · 2025: 2 · 2024: 11 · 2023: 6 · 2022: 10 · 2021: 15 · 2020: 11 · 2019: 15 · 2018: 15 · 2017: 25 · 2016: 24 · 2015: 18 · 2014: 2
FWCI
9.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • Figshare (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
Funders
  • Wellcome Trust (G0700089, GR082557)
  • National Institutes of Health
  • Medical Research Council (MC_PC_15004, MR/K013807/1, K013807)
  • National Institute on Aging (R01AG036039, AG036039)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
schizophrenia, DNA methylation, epigenetics, brain development, prefrontal cortex, cerebellum, fetal brain development, differentially methylated positions
MeSH terms
Brain, Cerebellum, Humans, Schizophrenia, Prefrontal Cortex, DNA Methylation, Epigenesis, Genetic, Fetal Development

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