Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A higher dysregulation burden of brain DNA methylation in female patients implicated in the sex bias of Schizophrenia

Abstract

Sex differences are pervasive in schizophrenia (SCZ), but the extent and magnitude of DNA methylation (DNAm) changes underlying these differences remain uncharacterized. In this study, sex-stratified differential DNAm analysis was performed in postmortem brain samples from 117 SCZ and 137 controls, partitioned into discovery and replication datasets. Three differentially methylated positions (DMPs) were identified (adj.p < 0.05) in females and 29 DMPs in males without overlap between them. Over 81% of these sex-stratified DMPs were directionally consistent between sexes but with different effect sizes. Females experienced larger magnitude of DNAm changes and more DMPs (based on data of equal sample size) than males, contributing to a higher dysregulation burden of DNAm in females SCZ. Additionally, despite similar proportions of female-related DMPs (fDMPs, 8%) being under genetic control compared with males (10%), significant enrichment of DMP-related single nucleotide polymorphisms (SNPs) in signals of genome-wide association studies was identified only in fDMPs. One DMP in each sex connected the SNPs and gene expression of CALHM1 in females and CCDC149 in males. PPI subnetworks revealed that both female- and male-related differential DNAm interacted with synapse-related dysregulation. Immune-related pathways were unique for females and neuron-related pathways were associated with males. This study reveals remarkable quantitative differences in DNAm-related sexual dimorphism in SCZ and that females have a higher dysregulation burden of SCZ-associated DNAm than males.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sex-stratified differential DNAm in SCZ.
Fig. 2: Comparing the magnitude of DNAm changes between females and males with SCZ.
Fig. 3: Sex-stratified DMPs mediate genetic effects on gene expression.
Fig. 4: Sex-specific PPI subnetworks and biological processes.
Fig. 5: The theoretical model for sex-biased DNAm burden hypothesis of SCZ.

Data availability

All data are available in the main text or the supplementary materials. Published DNAm datasets analyzed in this study are available on Gene Expression Omnibus (accession No. GSE74193, GSE61431 and GSE61380).

Code availability

The code of this work can be found at https://github.com/zhoujiaqi704/Sex-stratified-differential-DNAm-in-schizophrenia.

References

  1. Castle DJ, Murray RM. The neurodevelopmental basis of sex differences in schizophrenia. Psychol Med. 1991;21:565–75.

    Article  CAS  PubMed  Google Scholar 

  2. Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl. 2000;401:3–38.

    Article  CAS  PubMed  Google Scholar 

  3. Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry. 2010;22:417–28.

    Article  PubMed  Google Scholar 

  4. Aleman A, Kahn RS, Selten JP. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry. 2003;60:565–71.

    Article  PubMed  Google Scholar 

  5. Bergen SE, O’Dushlaine CT, Lee PH, Fanous AH, Ruderfer DM, Ripke S, et al. Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history. Schizophr Res. 2014;154:48–53.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Walder DJ, Seidman LJ, Cullen N, Su J, Tsuang MT, Goldstein JM. Sex differences in language dysfunction in schizophrenia. Am J Psychiatry. 2006;163:470–7.

    Article  PubMed  Google Scholar 

  7. Morgan VA, Castle DJ, Jablensky AV. Do women express and experience psychosis differently from men? Epidemiological evidence from the Australian National Study of Low Prevalence (Psychotic) disorders. Aust N. Z J Psychiatry. 2008;42:74–82.

    Article  PubMed  Google Scholar 

  8. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry. 2004;161:1324–33.

    Article  PubMed  Google Scholar 

  9. Smith S. Gender differences in antipsychotic prescribing. Int Rev Psychiatry. 2010;22:472–84.

    Article  PubMed  Google Scholar 

  10. Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet. 2014;94:415–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goldstein JM, Cherkerzian S, Tsuang MT, Petryshen TL. Sex differences in the genetic risk for schizophrenia: history of the evidence for sex-specific and sex-dependent effects. Am J Med Genet B Neuropsychiatr Genet. 2013;162b:698–710.

    Article  PubMed  Google Scholar 

  12. Sham PC, MacLean CJ, Kendler KS. A typological model of schizophrenia based on age at onset, sex and familial morbidity. Acta Psychiatr Scand. 1994;89:135–41.

    Article  CAS  PubMed  Google Scholar 

  13. Kubota T, Miyake K, Hirasawa T. Epigenetic understanding of gene-environment interactions in psychiatric disorders: a new concept of clinical genetics. Clin Epigenet. 2012;4:1.

    Article  CAS  Google Scholar 

  14. Qureshi IA, Mehler MF. Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility. Prog Brain Res. 2010;186:77–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xia Y, Dai R, Wang K, Jiao C, Zhang C, Xu Y et al. Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders. Mol Psychiatry. 2019.

  16. Maschietto M, Bastos LC, Tahira AC, Bastos EP, Euclydes VL, Brentani A, et al. Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases. Sci Rep. 2017;7:44547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Singmann P, Shem-Tov D, Wahl S, Grallert H, Fiorito G, Shin SY, et al. Characterization of whole-genome autosomal differences of DNA methylation between men and women. Epigenet Chromatin. 2015;8:43.

    Article  Google Scholar 

  18. Yousefi P, Huen K, Davé V, Barcellos L, Eskenazi B, Holland N. Sex differences in DNA methylation assessed by 450 K BeadChip in newborns. BMC Genom. 2015;16:911.

    Article  Google Scholar 

  19. Xu H, Wang F, Liu Y, Yu Y, Gelernter J, Zhang H. Sex-biased methylome and transcriptome in human prefrontal cortex. Hum Mol Genet. 2014;23:1260–70.

    Article  CAS  PubMed  Google Scholar 

  20. McCarthy NS, Melton PE, Cadby G, Yazar S, Franchina M, Moses EK, et al. Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns. BMC Genom. 2014;15:981.

    Article  Google Scholar 

  21. Spiers H, Hannon E, Schalkwyk LC, Smith R, Wong CC, O’Donovan MC, et al. Methylomic trajectories across human fetal brain development. Genome Res. 2015;25:338–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khramtsova EA, Davis LK, Stranger BE. The role of sex in the genomics of human complex traits. Nat Rev Genet. 2019;20:173–90.

    Article  CAS  PubMed  Google Scholar 

  23. McCarthy MM, Nugent BM, Lenz KM. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat Rev Neurosci. 2017;18:471–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Montano C, Taub MA, Jaffe A, Briem E, Feinberg JI, Trygvadottir R, et al. Association of DNA Methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry. 2016;73:506–14.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82:696–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Athar A, Fullgrabe A, George N, Iqbal H, Huerta L, Ali A, et al. ArrayExpress update - from bulk to single-cell expression data. Nucleic Acids Res. 2019;47:D711–D715.

    Article  CAS  PubMed  Google Scholar 

  28. Jaffe AE, Gao Y, Deep-Soboslay A, Tao R, Hyde TM, Weinberger DR, et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci. 2016;19:40–47.

    Article  CAS  PubMed  Google Scholar 

  29. Pidsley R, Viana J, Hannon E, Spiers H, Troakes C, Al-Saraj S, et al. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol. 2014;15:483.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tian Y, Morris TJ, Webster AP, Yang Z, Beck S, Feber A, et al. ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics. 2017;33:3982–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhou W, Laird PW, Shen H. Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes. Nucleic Acids Res. 2017;45:e22.

    PubMed  Google Scholar 

  32. Nordlund J, Bäcklin CL, Wahlberg P, Busche S, Berglund EC, Eloranta ML, et al. Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. Genome Biol. 2013;14:r105.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pidsley R, Y Wong CC, Volta M, Lunnon K, Mill J, Schalkwyk LC. A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genom. 2013;14:293.

    Article  CAS  Google Scholar 

  34. Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013;29:189–96.

    Article  CAS  PubMed  Google Scholar 

  35. Naeem H, Wong NC, Chatterton Z, Hong MK, Pedersen JS, Corcoran NM, et al. Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array. BMC Genom. 2014;15:51.

    Article  Google Scholar 

  36. Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinform. 2012;13:86.

    Article  Google Scholar 

  37. 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;8:290–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jiao C, Zhang C, Dai R, Xia Y, Wang K, Giase G, et al. Positional effects revealed in Illumina methylation array and the impact on analysis. Epigenomics. 2018;10:643–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen C, Grennan K, Badner J, Zhang D, Gershon E, Jin L, et al. Removing batch effects in analysis of expression microarray data: an evaluation of six batch adjustment methods. PLoS One. 2011;6:e17238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Leek JT, Storey JD. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 2007;3:1724–35.

    Article  CAS  PubMed  Google Scholar 

  41. Plaisier SB, Taschereau R, Wong JA, Graeber TG. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 2010;38:e169.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ng B, White CC, Klein HU, Sieberts SK, McCabe C, Patrick E, et al. An xQTL map integrates the genetic architecture of the human brain’s transcriptome and epigenome. Nat Neurosci. 2017;20:1418–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang K, Dai R, Xia Y, Tian J, Jiao C, Mikhailova T et al. Spatiotemporal specificity of correlated DNA methylation and gene expression pairs across different human tissues and stages of brain development. Epigenetics. 2021:1-18.

  45. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jiao Y, Widschwendter M, Teschendorff AE. A systems-level integrative framework for genome-wide DNA methylation and gene expression data identifies differential gene expression modules under epigenetic control. Bioinformatics. 2014;30:2360–6.

    Article  CAS  PubMed  Google Scholar 

  47. Cerami EG, Gross BE, Demir E, Rodchenkov I, Babur O, Anwar N, et al. Pathway commons, a web resource for biological pathway data. Nucleic Acids Res. 2011;39:D685–690.

    Article  CAS  PubMed  Google Scholar 

  48. West J, Beck S, Wang X, Teschendorff AE. An integrative network algorithm identifies age-associated differential methylation interactome hotspots targeting stem-cell differentiation pathways. Sci Rep. 2013;3:1630.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 2012;16:284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Seney ML, Huo Z, Cahill K, French L, Puralewski R, Zhang J, et al. Opposite molecular signatures of depression in men and women. Biol Psychiatry. 2018;84:18–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550:244–8.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mignot C, McMahon AC, Bar C, Campeau PM, Davidson C, Buratti J, et al. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genet Med. 2019;21:837–49.

    Article  CAS  PubMed  Google Scholar 

  54. Decarpentrie F, Vernet N, Mahadevaiah SK, Longepied G, Streichemberger E, Aknin-Seifer I, et al. Human and mouse ZFY genes produce a conserved testis-specific transcript encoding a zinc finger protein with a short acidic domain and modified transactivation potential. Hum Mol Genet. 2012;21:2631–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Trubetskoy V, Pardinas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022;604:502–8.

  56. Chen C, Meng Q, Xia Y, Ding C, Wang L, Dai R, et al. The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders. Sci Transl Med. 2018;10:eaat8178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ding C, Zhang C, Kopp R, Kuney L, Meng Q, Wang L, et al. Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia. Mol Psychiatry. 2021;26:3444–60.

    Article  PubMed  Google Scholar 

  58. Tanis JE, Ma Z, Krajacic P, He L, Foskett JK, Lamitina T. CLHM-1 is a functionally conserved and conditionally toxic Ca2+-permeable ion channel in Caenorhabditis elegans. J Neurosci. 2013;33:12275–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rusakov DA, Fine A. Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron. 2003;37:287–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Guan F, Zhang T, Li L, Fu D, Lin H, Chen G, et al. Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population. Schizophr Res. 2016;176:125–30.

    Article  PubMed  Google Scholar 

  62. Christoforou A, Le Hellard S, Thomson PA, Morris SW, Tenesa A, Pickard BS, et al. Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia. Mol Psychiatry. 2007;12:1011–25.

    Article  CAS  PubMed  Google Scholar 

  63. Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM, Mahurkar A, et al. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci. 2015;18:690–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Markham JA. Sex steroids and schizophrenia. Rev Endocr Metab Disord. 2012;13:187–207.

    Article  CAS  PubMed  Google Scholar 

  65. Tang S, Han H, Bajic VB. ERGDB: estrogen responsive genes database. Nucleic Acids Res. 2004;32:D533–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jiang M, Ma Y, Chen C, Fu X, Yang S, Li X, et al. Androgen-responsive gene database: integrated knowledge on androgen-responsive genes. Mol Endocrinol. 2009;23:1927–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Blokland GAM, Grove J, Chen CY, Cotsapas C, Tobet S, Handa R, et al. Sex-dependent shared and nonshared genetic architecture across mood and psychotic disorders. Biol Psychiatry. 2022;91:102–17.

    Article  CAS  PubMed  Google Scholar 

  68. Martin J, Khramtsova EA, Goleva SB, Blokland GAM, Traglia M, Walters RK, et al. Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits. Biol Psychiatry. 2021;89:1127–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Polderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015;47:702–9.

    Article  CAS  PubMed  Google Scholar 

  70. Oliva M, Munoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, et al. The impact of sex on gene expression across human tissues. Science. 2020;369:eaba3066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hoffman GE, Ma Y, Montgomery KS, Bendl J, Jaiswal MK, Kozlenkov A, et al. Sex differences in the human brain transcriptome of cases with schizophrenia. Biol Psychiatry. 2022;91:92–101.

    Article  CAS  PubMed  Google Scholar 

  72. Wijchers PJ, Festenstein RJ. Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 2011;27:132–40.

    Article  CAS  PubMed  Google Scholar 

  73. Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci. 2016;19:48–54.

    Article  CAS  PubMed  Google Scholar 

  74. Perzel Mandell KA, Eagles NJ, Wilton R, Price AJ, Semick SA, Collado-Torres L, et al. Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk. Nat Commun. 2021;12:5251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gamazon ER, Badner JA, Cheng L, Zhang C, Zhang D, Cox NJ, et al. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry. 2013;18:340–6.

    Article  CAS  PubMed  Google Scholar 

  76. Nelson LH, Saulsbery AI, Lenz KM. Small cells with big implications: Microglia and sex differences in brain development, plasticity and behavioral health. Prog Neurobiol. 2019;176:103–19.

    Article  PubMed  Google Scholar 

  77. Frye HE, Izumi Y, Harris AN, Williams SB, Trousdale CR, Sun MY, et al. Sex differences in the role of CNIH3 on spatial memory and synaptic plasticity. Biol Psychiatry. 2021;90:766–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen Y, Dai J, Tang L, Mikhailova T, Liang Q, Li M, et al. Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders. Mol Psychiatry. 2023;28:710–21.

  80. Alonso-Nanclares L, Gonzalez-Soriano J, Rodriguez JR, DeFelipe J. Gender differences in human cortical synaptic density. Proc Natl Acad Sci USA. 2008;105:14615–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cooke BM, Woolley CS. Sexually dimorphic synaptic organization of the medial amygdala. J Neurosci. 2005;25:10759–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Uhl M, Schmeisser MJ, Schumann S. The sexual dimorphic synapse: from spine density to molecular composition. Front Mol Neurosci. 2022;15:818390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Richard F. Kopp from SUNY Upstate Medical University, for his critical reading and language editing, which greatly improved the manuscript. We gratefully acknowledge the families of the brain donors, without whom this work would not have been possible. This work was supported in part by the High Performance Computing Center of Central South University.

Funding

FundingThis work was supported by the National Natural Science Foundation of China (Grants Nos. 82022024, 31970572, 31871276), the National Key R&D Project of China (Grants No. 2016YFC1306000), the science and technology innovation Program of Hunan Province, Innovation-driven Project of Central South University (Grant Nos. 2020CX003) (to C. Chen), and NIH grants U01MH122591, 1U01MH116489, 1R01MH110920 (to C. Liu).

Author information

Authors and Affiliations

Authors

Contributions

CL, CC and YX designed and guided the study. JZ and ML collected and download the datasets. JZ, ML and YC preprocessed the data. JZ, ML, YC and JD did the bioinformatics analyses. JZ wrote the manuscript with substantive edits from CL, CC, YX and YC.

Corresponding authors

Correspondence to Yan Xia, Chunyu Liu or Chao Chen.

Ethics declarations

Competing interests

The authors declare no cmpeting interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, J., Xia, Y., Li, M. et al. A higher dysregulation burden of brain DNA methylation in female patients implicated in the sex bias of Schizophrenia. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02243-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-023-02243-4

Search

Quick links