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Epigenetics Volume 16, 2021 - Issue 8
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Research Paper

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Dongdong Lina Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USAView further author information
,
Jiayu Chena Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USAView further author information
,
Kuaikuai Duanb Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, USAView further author information
,
Nora Perrone-Bizzozeroc Department of Neurosciences, University of New Mexico, Albuquerque, NM, USA;d Department of Psychiatry, University of New Mexico, Albuquerque, NM, USAView further author information
,
Jing Suia Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USAORCID Iconhttps://orcid.org/0000-0001-6837-5966View further author information
ORCID Icon,
Vince Calhouna Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA;b Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, USA;e Department of Psychology, Georgia State University, Atlanta, USA;f Department of Computer Science, Georgia State University, Atlanta, USAView further author information
&
Jingyu Liua Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA;f Department of Computer Science, Georgia State University, Atlanta, USACorrespondence[email protected]
View further author information
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Pages 876-893 | Received 03 Jun 2020, Accepted 21 Aug 2020, Published online: 20 Oct 2020

  • Mathers C, Fat DM, Boerma JT. The global burden of disease: 2004 update. Geneva: World Health Organization; 2008.
  • Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187–1192.
  • Gupta CN, Calhoun VD, Rachakonda S, et al. Patterns of gray matter abnormalities in schizophrenia based on an international mega-analysis. Schizophr Bull. 2015;41(5):1133–1142.
  • Romme IA, de Reus MA, Ophoff RA, et al. Connectome disconnectivity and cortical gene expression in patients with schizophrenia. Biol Psychiatry. 2017;81(6):495–502.
  • Calhoun VD, Eichele T, Pearlson G. Functional brain networks in schizophrenia: a review. Front Hum Neurosci. 2009;3:17.
  • Flynn SW, Lang DJ, Mackay AL, et al. Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol Psychiatry. 2003;8(9):811–820.
  • Kelly S, Jahanshad N, Zalesky A, et al. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Mol Psychiatry. 2018;23(5):1261–1269.
  • Keefe RS, Harvey PD Cognitive impairment in schizophrenia. In: Novel antischizophrenia treatments. Berlin, Heidelberg: Springer; 2012. p. 11–37.
  • Bale TL, Baram TZ, Brown AS, et al. Early life programming and neurodevelopmental disorders. Biol Psychiatry. 2010;68(4):314–319.
  • Horvath S, Janka Z, Mirnics K. Analyzing schizophrenia by DNA microarrays. Biol Psychiatry. 2011;69(2):157–162.
  • Dixon AL, Liang L, Moffatt MF, et al. A genome-wide association study of global gene expression. Nat Genet. 2007;39(10):1202.
  • Stranger BE, Raj T. Genetics of human gene expression. Curr Opin Genet Dev. 2013;23(6):627–634.
  • Ripke S, Neale BM, Corvin A, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421.
  • Jaffe AE, Straub RE, Shin JH, et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat Neurosci. 2018;21(8):1117–1125.
  • Fromer M, Roussos P, Sieberts SK, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19(11):1442–1453.
  • Radulescu E, Jaffe AE, Straub RE, et al. Identification and prioritization of gene sets associated with schizophrenia risk by co-expression network analysis in human brain. Mol Psychiatry. 2020;25:791–804.
  • Katsel P, Davis KL, Gorman JM, et al. Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizophr Res. 2005;77(2–3):241–252.
  • Gandal MJ, Haney JR, Parikshak NN, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359(6376):693–697.
  • Torkamani A, Dean B, Schork NJ, et al. Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Res. 2010;20(4):403–412.
  • Nowakowski TJ, Bhaduri A, Pollen AA, et al. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science. 2017;358(6368):1318–1323.
  • Aberg KA, McClay JL, Nerella S, et al. Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry. 2014;71(3):255–264.
  • Vogel Ciernia A, LaSalle J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci. 2016;17(7):411–423.
  • Ramchandani S, Bhattacharya SK, Cervoni N, et al. DNA methylation is a reversible biological signal. Proc Nat Acad Sci. 1999;96(11):6107–6112.
  • Yao B, Christian KM, He C, et al. Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci. 2016;17(9):537–549.
  • Delgado-Morales R, Agis-Balboa RC, Esteller M, et al. Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics. 2017;9:67.
  • Jaffe AE, Gao Y, Deep-Soboslay A, et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci. 2016;19(1):40–47.
  • Hannon E, Spiers H, Viana J, et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci. 2016;19(1):48.
  • Andrews SV, Ellis SE, Bakulski KM, et al. Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder. Nat Commun. 2017;8(1):1011.
  • Lin D, Chen J, Perrone-Bizzozero N, et al. Characterization of cross-tissue genetic-epigenetic effects and their patterns in schizophrenia. Genome Med. 2018;10(1):13.
  • Lipska BK, Deep-Soboslay A, Weickert CS, et al. Critical factors in gene expression in postmortem human brain: focus on studies in schizophrenia. Biol Psychiatry. 2006;60(6):650–658.
  • Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
  • Hemani G, Shakhbazov K, Westra HJ, et al. Detection and replication of epistasis influencing transcription in humans. Nature. 2014;508(7495):249–253.
  • Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8(1):118–127.
  • Leek JT, Johnson WE, Parker HS, et al. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28(6):882–883.
  • Aryee MJ, Jaffe AE, Corrada-Bravo H, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30(10):1363–1369.
  • Lin D, Chen J, Ehrlich S, et al. Cross-Tissue exploration of genetic and epigenetic effects on brain gray matter in schizophrenia. Schizophr Bull. 2018;44:443–452.
  • Chen YA, Lemire M, Choufani S, et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics. 2013;8(2):203–209.
  • Naeem H, Wong NC, Chatterton Z, et al. Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array. BMC Genomics. 2014;15(1):51.
  • Rahmani E, Yedidim R, Shenhav L, et al. GLINT: a user-friendly toolset for the analysis of high-throughput DNA-methylation array data. Bioinformatics. 2017;33(12):1870–1872.
  • Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9(1):559.
  • Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190–2191.
  • Durinck S, Spellman PT, Birney E, et al. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4(8):1184–1191.
  • Hernandez DG, Nalls MA, Moore M, et al. Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain. Neurobiol Dis. 2012;47(1):20–28.
  • Gibbs JR, van der Brug MP, Hernandez DG, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952.
  • Narayan S, Tang B, Head SR, et al. Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res. 2008;1239:235–248.
  • McGirr A, Tousignant M, Routhier D, et al. Risk factors for completed suicide in schizophrenia and other chronic psychotic disorders: a case-control study. Schizophr Res. 2006;84(1):132–143.
  • Onnela JP, Saramaki J, Kertesz J, et al. Intensity and coherence of motifs in weighted complex networks. Phys Rev E Stat Nonlin Soft Matter Phys. 2005;71(6 Pt 2):065103.
  • Langfelder P, Luo R, Oldham MC, et al. Is my network module preserved and reproducible? PLoS Comput Biol. 2011;7(1):e1001057.
  • Dougherty JD, Schmidt EF, Nakajima M, et al. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 2010;38(13):4218–4230.
  • Zhang Y, Sloan SA, Clarke LE, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016;89(1):37–53.
  • Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8(3):290–302.
  • Ripke S, Sanders AR, Kendler KS, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43(10):969.
  • Radulescu E, Jaffe AE, Straub RE, et al. Identification and prioritization of gene sets associated with schizophrenia risk by co-expression network analysis in human brain. bioRxiv, 2018
  • Bernstein H-G, Steiner J, Guest PC, et al. Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res. 2015;161(1):4–18.
  • Solberg D, Bentsen H, Refsum H, et al. Association between serum lipids and membrane fatty acids and clinical characteristics in patients with schizophrenia. Acta Psychiatr Scand. 2015;132(4):293–300.
  • Sumiyoshi T, Anil AE, Jin D, et al. Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms. Int J Neuropsychopharmacol. 2004;7(1):1–8.
  • Marsman A, van den Heuvel MP, Klomp DW, et al. Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull. 2011;39(1):120–129.
  • Chiappelli J, Postolache TT, Kochunov P, et al. Tryptophan metabolism and white matter integrity in schizophrenia. Neuropsychopharmacology. 2016;41(10):2587.
  • Erickson MA, Dohi K, Banks WA. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation. 2012;19(2):121–130.
  • Weksler B, Subileau E, Perriere N, et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. Faseb J. 2005;19(13):1872–1874.
  • Streit WJ, Mrak RE, Griffin WST. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation. 2004;1(1):14.
  • Khandaker GM, Cousins L, Deakin J, et al. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258–270.
  • Monji A, Kato TA, Mizoguchi Y, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuro Psychopharmacol Biol Psychiatry. 2013;42:115–121.
  • Choudary PV, Molnar M, Evans SJ, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A. 2005;102(43):15653–15658.
  • Cahoy JD, Emery B, Kaushal A, et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28(1):264–278.
  • Blum BP, Mann JJ. The GABAergic system in schizophrenia. Int J Neuropsychopharmacol. 2002;5(2):159–179.
  • Ruzicka WB, Subburaju S, Benes FM. Circuit- and diagnosis-specific DNA methylation changes at gamma-aminobutyric acid-related genes in postmortem human hippocampus in schizophrenia and bipolar disorder. JAMA Psychiatry. 2015;72(6):541–551.
  • Aghajanian GK, Marek GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev. 2000;31(2–3):302–312.
  • Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013;14(11):1225–1236.
  • Nagy C, Suderman M, Yang J, et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol Psychiatry. 2015;20(3):320–328.
  • Hannon E, Dempster E, Viana J, et al. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 2016;17(1):176.
  • Montano C, Taub MA, Jaffe A, et al. Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry. 2016;73(5):506–514.
  • Maekawa M, Watanabe A, Iwayama Y, et al. Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes. Transl Psychiatry. 2017;7(9):e1229.
  • Gamazon E, Badner J, Cheng L, et al. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry. 2013;18(3):340–346.
  • Numata S, Ye T, Herman M, et al. DNA methylation changes in the postmortem dorsolateral prefrontal cortex of patients with schizophrenia. Front Genet. 2014;5:280.
  • Banovich NE, Lan X, McVicker G, et al. Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet. 2014;10(9):e1004663.
  • Gibson EM, Purger D, Mount CW, et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science. 2014;344(6183):1252304.
  • Fields RD. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. Neuroscientist. 2008;14(6):540–543.
  • Hagmann P, Sporns O, Madan N, et al. White matter maturation reshapes structural connectivity in the late developing human brain. Proc Natl Acad Sci U S A. 2010;107(44):19067–19072.
  • Simons M, Nave K-A. Oligodendrocytes: myelination and axonal support. Cold Spring Harb Perspect Biol. 2016;8(1):a020479.
  • Sim FJ, Zhao C, Penderis J, et al. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci. 2002;22(7):2451–2459.
  • Hakak Y, Walker JR, Li C, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A. 2001;98(8):4746–4751.
  • Shen S, Sandoval J, Swiss VA, et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci. 2008;11(9):1024.
  • Emery B, Agalliu D, Cahoy JD, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell. 2009;138(1):172–185.
  • Liu J, Moyon S, Hernandez M, et al. Epigenetic control of oligodendrocyte development: adding new players to old keepers. Curr Opin Neurobiol. 2016;39:133–138.
  • Copray S, Huynh JL, Sher F, et al. Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging. Glia. 2009;57(15):1579–1587.
  • Cole JH, Marioni RE, Harris SE, et al. Brain age and other bodily ‘ages’: implications for neuropsychiatry. Mol Psychiatry. 2019;24(2):266–281.
  • Higgins-Chen AT, Boks MP, Vinkers CH, et al. Schizophrenia and epigenetic aging biomarkers: increased mortality, reduced cancer risk, and unique clozapine effects. Biological Psychiatry. 2020;88(3):224–235.
  • Schnack HG, Van Haren NE, Nieuwenhuis M, et al. Accelerated brain aging in schizophrenia: a longitudinal pattern recognition study. Am J Psychiatry. 2016;173(6):607–616.
  • Lin CW, Chang LC, Ma T, et al. Older molecular brain age in severe mental illness. Mol Psychiatry. 2020. DOI:10.1038/s41380-020-0834-1
  • Kaufmann T, van der Meer D, Doan NT, et al. Common brain disorders are associated with heritable patterns of apparent aging of the brain. Nat Neurosci. 2019;22(10):1617–1623.

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