Cell-type-resolved DNA methylation profiling in the cortex reveals female-specific X chromosome differences in autism
- 1University of Exeter
Abstract
Sex differences are a prominent feature of many neurodevelopmental conditions, particularly autism for which approximately three males are diagnosed for every female. Although epigenetic dysregulation has been implicated in autism, the extent to which autism-associated epigenetic differences vary by sex and neural cell type remains poorly understood. Using fluorescence-activated nuclei sorting (FANS), we isolated neuron-enriched (NeuN+), oligodendrocyte-enriched (SOX10+), microglia-enriched (IRF8+) and astrocyte-enriched (NeuN-/SOX10-/IRF8-) nuclei from post-mortem prefrontal cortex tissue from 24 autistic (70.8% male) and 23 non-autistic (69.6% male) donors, and performed cell-type-resolved epigenome-wide association studies (EWASs) of DNA methylation. We identified cell-type-specific autism-associated differentially methylated positions (DMPs), with microglia harbouring the largest number of associations. Modelling the interaction between sex and diagnosis revealed a striking female-specific signature concentrated on the X chromosome in microglia. At the majority of these sex-by-autism DMPs, autistic females showed lower DNA methylation compared to control females consistent with an altered X chromosome inactivation (XCI) profile. Across the X chromosome, autism-associated DNA methylation differences were significantly larger in females than males and were greater at sites annotated to genes normally subject to XCI than at genes that escape XCI. Together, these data further support the importance of microglia in autism and suggest that altered X chromosome dosage regulation may contribute to sex-dependent molecular mechanisms in autism.
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BibTeX
@misc{franklin2026celltyperesolved,
title = {{Cell-type-resolved DNA methylation profiling in the cortex reveals female-specific X chromosome differences in autism}},
author = {A. Franklin and J. P. Davies and B. Chioza and J. Burrage and E. M. Walker and R. Bamford and A. C. Babtie and G. E. T. Blake and The APEX Consortium and S. Baron-Cohen and E. L. Dempster and E. Hannon and J. Mill},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.749446},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.749446v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cell-type-resolved DNA methylation profiling in the cortex reveals female-specific X chromosome differences in autism
AU - A. Franklin
AU - J. P. Davies
AU - B. Chioza
AU - J. Burrage
AU - E. M. Walker
AU - R. Bamford
AU - A. C. Babtie
AU - G. E. T. Blake
AU - The APEX Consortium
AU - S. Baron-Cohen
AU - E. L. Dempster
AU - E. Hannon
AU - J. Mill
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.749446
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.749446v1
AB - Sex differences are a prominent feature of many neurodevelopmental conditions, particularly autism for which approximately three males are diagnosed for every female. Although epigenetic dysregulation has been implicated in autism, the extent to which autism-associated epigenetic differences vary by sex and neural cell type remains poorly understood. Using fluorescence-activated nuclei sorting (FANS), we isolated neuron-enriched (NeuN+), oligodendrocyte-enriched (SOX10+), microglia-enriched (IRF8+) and astrocyte-enriched (NeuN-/SOX10-/IRF8-) nuclei from post-mortem prefrontal cortex tissue from 24 autistic (70.8% male) and 23 non-autistic (69.6% male) donors, and performed cell-type-resolved epigenome-wide association studies (EWASs) of DNA methylation. We identified cell-type-specific autism-associated differentially methylated positions (DMPs), with microglia harbouring the largest number of associations. Modelling the interaction between sex and diagnosis revealed a striking female-specific signature concentrated on the X chromosome in microglia. At the majority of these sex-by-autism DMPs, autistic females showed lower DNA methylation compared to control females consistent with an altered X chromosome inactivation (XCI) profile. Across the X chromosome, autism-associated DNA methylation differences were significantly larger in females than males and were greater at sites annotated to genes normally subject to XCI than at genes that escape XCI. Together, these data further support the importance of microglia in autism and suggest that altered X chromosome dosage regulation may contribute to sex-dependent molecular mechanisms in autism.
ER -