{ "abstract": "Autism spectrum disorder (ASD) is highly heritable, and mutations in hundreds of genes have been implicated as individually rare causes of ASD 1–3 . Understanding how disruptions to these functionally diverse genes lead to the core features of ASD remains a major challenge 4 . Moreover, ASD is three- to four-fold more common in males than females 5 , and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males 6,7 , but the biological basis of this “female protective effect” (FPE) is unknown 8,9 . Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST , that drive this transcriptomic convergence. Furthermore, the X-linked transcription factor ZFX , which is expressed from both the active and the inactive X chromosomes in females 10 , emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.", "abstract_shown": true, "affiliations": [ "Allen Discovery Center for Human Brain Evolution, Boston, MA, USA. becky.e.andersen@gmail.com", "Broad Institute of MIT and Harvard, Cambridge, MA, USA. becky.e.andersen@gmail.com", "Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. becky.e.andersen@gmail.com", "Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA. becky.e.andersen@gmail.com", "Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. becky.e.andersen@gmail.com", "Boston Children's Hospital", "Broad Institute of MIT and Harvard, Cambridge, MA, USA", "Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA", "Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA", "Harvard-MIT MD/PhD Program and Harvard PhD Program in Biomedical Informatics, Harvard Medical School, Boston, MA, USA", "Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA", "Whitehead Institute, Cambridge, MA, USA", "Harvard Medical School", "Harvard College, Cambridge, MA, USA", "Allen Discovery Center for Human Brain Evolution, Boston, MA, USA", "Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA", "Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA", "University of Massachusetts Boston, Boston, MA, USA", "Department of Genetics, Blavatnik Institute and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA", "Colgate University", "Harvard BBS PhD Program, Harvard Medical School, Boston, MA, USA", "University of California, Berkeley", "Colgate University, Hamilton, NY, USA", "University of California Berkeley, Berkeley, CA, USA", "Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA", "Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA", "Allen Discovery Center for Human Brain Evolution, Boston, MA, USA. christopher.walsh@childrens.harvard.edu", "Broad Institute of MIT and Harvard, Cambridge, MA, USA. christopher.walsh@childrens.harvard.edu", "Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. christopher.walsh@childrens.harvard.edu", "Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA. christopher.walsh@childrens.harvard.edu", "Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. christopher.walsh@childrens.harvard.edu" ], "article_type": null, "arxiv": null, "author_total": 14, "authors": [ { "affs": [ 0, 1, 2, 3, 4, 5 ], "name": "Rebecca Andersen", "orcid": "0000-0002-0702-3120" }, { "affs": [ 6, 7, 8, 9, 10, 11, 12 ], "name": "Maya Talukdar", "orcid": "0000-0002-5997-5633" }, { "affs": [ 7, 8, 13, 10, 5 ], "name": "Tyler Sakamoto", "orcid": "0009-0001-5972-8288" }, { "affs": [ 14, 7, 8, 10, 5 ], "name": "David Exposito-Alonso", "orcid": "0000-0002-4950-2744" }, { "affs": [ 14, 15, 7, 8, 10, 5 ], "name": "Janet H. T. Song", "orcid": "0000-0002-7898-0227" }, { "affs": [ 14, 16, 7, 8, 10, 5 ], "name": "Xuyu Qian", "orcid": "0000-0001-5944-3816" }, { "affs": [ 7, 8, 13, 10, 12 ], "name": "Seungil Lee", "orcid": "0000-0003-2829-2941" }, { "affs": [ 7, 8, 10, 17, 5 ], "name": "Nila Murugan" }, { "affs": [ 18, 19 ], "name": "Ryan Nicholas Delgado", "orcid": "0000-0002-7551-0182" }, { "affs": [ 7, 8, 20, 10, 21 ], "name": "Sijing Zhao", "orcid": "0000-0003-1247-6834" }, { "affs": [ 22, 7, 8, 10, 5 ], "name": "Gwenyth C. Eichfeld", "orcid": "0009-0007-6618-5406" }, { "affs": [ 7, 8, 10, 23 ], "name": "Julia Harms", "orcid": "0009-0006-7661-3083" }, { "affs": [ 24, 25, 11 ], "name": "David C. Page", "orcid": "0000-0001-9920-3411" }, { "affs": [ 26, 27, 28, 29, 30 ], "name": "Christopher A. Walsh", "orcid": "0000-0002-0156-2238" } ], "bibtex": "https://research.draconitic.com/paper/72c8pvcnsqbzt.bib", "cited_by": 9, "doi": "10.1038/s41586-026-11236-6", "fulltext_url": null, "id": "72c8pvcnsqbzt", "issns": [ "0028-0836", "1476-4687" ], "landing_url": "https://doi.org/10.1038/s41586-026-11236-6", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2805|Autism Spectrum Disorder Research" ] ], "openalex": "W4406697278", "pdf_url": "https://www.nature.com/articles/s41586-026-11236-6.pdf", "pmcid": "PMC11785016", "pmid": "39896631", "published": "2026-11-04", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/72c8pvcnsqbzt.ris", "sources": [ { "first_seen": "2026-11-06T13:20:36Z", "native_id": "W4406697278", "source": "openalex", "url": "https://doi.org/10.1038/s41586-026-11236-6" } ], "subjects": [ { "field": "biology", "origin": "openalex:2805|Autism Spectrum Disorder Research", "subfield": "neuroscience" } ], "title": "Transcriptomic convergence and the female protective effect in autism", "title_text": "Transcriptomic convergence and the female protective effect in autism", "type": "peer-reviewed", "updated_at": "2026-11-08T13:20:48Z", "url": "https://research.draconitic.com/paper/72c8pvcnsqbzt", "venue": "Nature", "versions": [] }