2026 ECNP Congress

PS02-2230

Age-dependent DNA methylation changes at FKBP5 enhancer sites are associated with increased cortical gene expression in schizophrenia

Natan Yusupov — K.Z. Edmond, D. Kaul, M. Ködel, S. Sauer, A.S. Fröhlich, J. Kentro, R. Tao, J.E. Kleinman, D.R. Weinberger, T.M. Hyde, D. Czamara, E.B. Binder, N. Matosin · Max Planck Institute of Psychiatry, Genes and Environment, Munich, Germany

2026 ECNP Congress

Objective: Stress-related psychiatric disorders represent a major global health burden [1]. Current therapeutic options largely focus on alleviating primary symptoms rather than targeting the underlying biological mechanisms that drive heterogeneous, patient-specific disease presentations [2] [3]. Advancing our understanding of the genetic and molecular bases of psychiatric disorders may enable mechanism-based diagnoses and the identification of biologically distinct patient subgroups for which tailored therapeutics may be most beneficial. An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) as a promising target for psychiatric therapeutics [4]. Increased mRNA expression of FKBP5 in postmortem brains with psychiatric diagnosis (specifically schizophrenia, major depressive disorder and post-traumatic stress disorder) and ageing have been reported previously [5] [6] [7] [8]. The genetic, endocrine and epigenetic mechanisms are hypothesised to converge in individuals with the FKBP5 risk allele who experience early life adversity, resulting in prolonged glucocorticoid release via direct effects of FKBP51 within the GR complex, reducing the receptors affinity and activity, thereby impairing negative feedback [9]. The molecular, cellular and systemic consequences of this gene x environment interaction may contribute to increased vulnerability to psychopathology. Increased FKBP51 expression, however, not only affects GR signalling via protein-protein interactions, but also several other downstream pathways with disease relevance, including BDNF, calcineurin, NF-κB, mTOR, autophagy and others [10] [11] [12]. FKBP5 gene regulation is shaped by a complex interplay of genetic and epigenetic factors. The epigenetic mechanisms underlying these effects in the human brain remain largely unknown.

Methods: We analysed previously generated DNA methylation array, single nucleotide polymorphism genotyping, bulk RNA-, single-nucleus RNA- and single-nucleus ATAC-sequencing data to examine FKBP5 DNA methylation patterns in postmortem human brain samples from the frontal cortex (dorsolateral prefrontal cortex and orbitofrontal cortex) of individuals who lived with a major psychiatric disorder (schizophrenia, major depressive disorder, or bipolar disorder) across two independent cohorts from the Lieber Institute for Brain Development Repository and the NSW Brain Tissue Resource Centre at the University of Sydney (n=378 cases and n=209 controls).

Results: We identified a number of cytosine-phosphate-guanine-dinucleotides (CpGs) across the proximal enhancer of the FKBP5 locus where DNA methylation negatively correlated with gene expression, with validation across both cohorts. Data from single-nucleus analyses support that these associations are relevant across all major cell types. In this functional region, as well as additional sites, we observed associations with age, rs1360780 genotype (CC vs CT/TT) and psychiatric diagnosis. Notably, individuals with schizophrenia exhibited significantly lower DNA methylation levels in the proximal enhancer region that showed additional converging effects of age and genotype, specifically in glucocorticoid response element-associated CpG sites.

Conclusions: This evidence supports that, in the human frontal cortex, ageing and psychiatric diagnosis associate with changes in FKBP5 DNA methylation in functionally relevant regulatory elements. This suggests that related changes in FKBP5 mRNA levels may be mediated by these epigenetic mechanisms. Such detailed understanding of increased FKBP5 expression in the brain will inform the development of FKBP5-targeted therapeutics for a defined subgroup of patients.

References

  1. Ferrari A, Santomauro D, Mantilla Herrera A, Shadid J, Erskine H, Charlson F, et al. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022; 9(2):137-50.
  2. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nature chemical biology. 2015; 11(1):33-7.
  3. Visscher PM, Wray NR, Zhang Q, Sklar P, McCarthy MI, Brown MA, et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet. 2017; 101(1):5-22.
  4. Matosin N, Halldorsdottir T, Binder EB. Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model. Biol Psychiatry 2018; 83:821-30.
  5. Matosin N, Arloth J, Czamara D, Edmond KZ, Maitra M, Fröhlich AS, et al. Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex. Acta Neuropathol. 2023; 145(4):439-59.
  6. Fröhlich AS, Gerstner N, Gagliardi M, Ködel M, Yusupov N, Matosin N, et al. Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease. Nat Neurosci. 2024; 27(10):2021-32.
  7. Hwang A, Skarica M, Xu S, Coudriet J, Lee CY, Lin L, et al. Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD. Nature. 2025; 643(8072):744-54.
  8. Daskalakis NP, Iatrou A, Chatzinakos C, Jajoo A, Snijders C, Wylie D, et al. Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood. Science. 2024; 384(6698):eadh3707.
  9. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat Neurosci. 2013; 16(1):33-41.
  10. Zannas AS, Wiechmann T, Gassen NC, Binder EB. Gene–Stress–Epigenetic Regulation of FKBP5: Clinical and Translational Implications. Neuropsychopharmacol. 2016; 41(1):261-74.
  11. Zannas AS, Jia M, Hafner K, Baumert J, Wiechmann T, Pape JC, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappaB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci U S A. 2019; 116(23):11370-9.
  12. Martinelli S, Anderzhanova EA, Bajaj T, Wiechmann S, Dethloff F, Weckmann K, et al. Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion. Nat Comms. 2021; 12(1).