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. 2021 Aug;13(15):1157-1169.
doi: 10.2217/epi-2021-0077. Epub 2021 Jul 29.

DNA methylation differences in cortical grey and white matter in schizophrenia

Amber Berdenis van Berlekom  1   2 , Nina Notman  1 , Marjolein Am Sneeboer  1   2 , Gijsje Jlj Snijders  1   3 , Lotte C Houtepen  1 , Danny M Nispeling  1 , Yujie He  1   2 , Stella Dracheva  4   3 , Elly M Hol  2 , René S Kahn  1   4   3 , Lot D de Witte  1   3 , Marco P Boks  1 ; Psychiatric Donor Program of the Netherlands Brain Bank (NBB-PSY)  5
Affiliations

DNA methylation differences in cortical grey and white matter in schizophrenia

Amber Berdenis van Berlekom et al. Epigenomics. 2021 Aug.

Abstract

Aim: Identify grey- and white-matter-specific DNA-methylation differences between schizophrenia (SCZ) patients and controls in postmortem brain cortical tissue. Materials & methods: Grey and white matter were separated from postmortem brain tissue of the superior temporal and medial frontal gyrus from SCZ (n = 10) and control (n = 11) cases. Genome-wide DNA-methylation analysis was performed using the Infinium EPIC Methylation Array (Illumina, CA, USA). Results: Four differentially methylated regions associated with SCZ status and tissue type (grey vs white matter) were identified within or near KLF9, SFXN1, SPRED2 and ALS2CL genes. Gene-expression analysis showed differential expression of KLF9 and SFXN1 in SCZ. Conclusion: Our data show distinct differences in DNA methylation between grey and white matter that are unique to SCZ, providing new leads to unravel the pathogenesis of SCZ.

Keywords: DNA-methylation; postmortem; schizophrenia.

Plain language summary

Lay abstract This study investigated the way gene activity is regulated in brain cells of patients with schizophrenia (SCZ; a severe mental illness characterized by psychosis) compared with unaffected controls. The study focuses on the differences between parts of the brain with many cell bodies (grey matter) in contrast to those parts with mainly conducting fibers (white matter). For that purpose, grey and white matter were separated from brain tissue of ten individuals with SCZ and 11 without. All brains were obtained after the patients died and donated their brains to science. Array technology was used to analyze 800,000 sections of the DNA at once. The study identified regions on four genes that can turn the genes on and off differently in schizophrenic patients compared with controls, these genes were also turned on or off depending on their location either in grey or white matter. Two of these genes showed different activation in schizophrenic patients compared with controls. Overall this study identified distinct differences between grey and white matter that are unique to SCZ, providing new leads to unravel the biology of SCZ.

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Conflict of interest statement

Financial & competing interests disclosure

S Dracheva is supported by VA Merit grant I01BX002876 and by NIH/NIMH U01MH116442. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Schematic overview of the study approach.
(A) Tissue from the GFM area 1 and 2 and GTS area 2–4 were obtained from SCZ (n = 12) and CTR (n = 14) donors, as indicated by the red circles. The Nissl staining shows grey and white matter, which were separated by hand and processed for DNA isolation and RNA isolation for DNA methylation analysis by the Infinium EPIC Methylation Array (Illumina, CA, USA) and gene expression analyses by qPCR, respectively. (B) Results from the DNA methylation array were analyzed in two steps. Step 1: the differences of CpG methylation between grey and white matter were assessed for SCZ and CTR donors separately and then compared. CPGs that differently regulated between grey and white matter in SCZ compared with CTR donors were selected. Examples are shown in the right panel. This analysis resulted in 24 DMRs. Step 2: for further gene expression analysis we selected DMRs that were significantly different when comparing grey and white matter and SCZ and CTR donors. Examples are shown in the right panel. There were four DMRs that met these criteria. CTR: Control; DMR: Differentially methylated region; GFM: Gyrus frontalis medialis; GTS: Gyrus temporalis superior; qPCR: Quantitative PCR; SCZ: Schizophrenia.
Figure 2.
Figure 2.. Gene expression in grey and white matter of the GFM and GTS in schizophrenia and control.
mRNA expression of genes was determined by qPCR in the GFM and GTS of SCZ patients (n = 11) and CTR donors (n = 14). Gene expression was normalized against reference genes βactin, SDHA, and GAPDH. Graphs show boxplots (white for CTR and grey for SCZ) containing individual data points for CTR (circles) and SCZ (squares) indicating the median, 25th and 75th percentile, with the whiskers showing the maximum and minimum values. Significance level was Bonferroni corrected and set to *p < 0.0042. CTR: Control; GFM: Gyrus frontalis medialis; GTS: Gyrus temporalis superior; qPCR: Quantitative PCR; SCZ: Schizophrenia.
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References

    1. Olabi B, Ellison-Wright I, McIntosh A, Wood S, Bullmore E, Lawrie S. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies Biol. Psychiatry 70, 88–96 (2011). - PubMed
    1. Wright I, Rabe-Hesketh S, Woodruff P, David A, Murray R, Bullmore E. Meta-analysis of regional brain volumes in schizophrenia. Am. J. Psychiatry 157, 16–25 (2000). - PubMed
    1. Cahn W, Van Haren NEM, Pol Het al.Brain volume changes in the first year of illness and 5-year outcome of schizophrenia. Br. J. Psychiatry 189, 381–382 (2006). - PubMed
    1. Haijma SV, Van Haren N, Cahn W, Koolschijn PCMP, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr. Bull. 39(5), 1129–1138 (2013). - PMC - PubMed
    1. Kyriakopoulos M, Vyas NS, Barker GJ, Chitnis XA, Frangou S. A diffusion tensor imaging study of white matter in early-onset schizophrenia. Biol. Psychiatry 63(5), 519–523 (2008). - PubMed

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