New Insights into the Genetic Underpinnings of Autism

Christopher Walsh’s lab at Boston Children’s Hospital has made significant strides in understanding the complex genetic landscape of autism spectrum disorder (ASD). A recent study, led by key investigator Rebecca Andersen, has shed new light on how a network of genes contributes to autism. This research, shared on bioRxiv in January 2025, involves knocking down 19 genes linked to autism and eight stretches of noncoding RNA to unravel their impact on brain cell development.

Understanding Christopher Walsh’s Lab

Christopher A. Walsh is a renowned expert in genetics and neurology at Harvard Medical School and Boston Children’s Hospital. His lab uses advanced genetic techniques to identify genes associated with neurological disorders like autism, epilepsy, and intellectual disability. By combining these techniques with insights into brain development, the lab aims to uncover the molecular mechanisms behind these conditions.

The Study: Unraveling Autism’s Genetic Network

The study focused on the intricate web of genes involved in autism. Here are the key points:

• CRISPR Technology: Researchers used CRISPR to knock down 19 autism-linked genes in human neural progenitor cells. This approach allowed them to see how each gene affects the expression of thousands of other genes.
• Gene Regulatory Network: The study identified a vast network involving 9,294 protein-coding genes and 161 long noncoding RNAs. Within this network, 78 genes regulate multiple autism-linked genes.
• Central Regulators: Genes like CHD8 (involved in chromatin remodeling) and REST (a neurogenesis regulator) were found to be central. ZFX, a transcription factor on the X chromosome, may help explain why autism is more common in males.
• Noncoding RNAs: Knocking down certain long noncoding RNAs altered the expression of neighboring genes, highlighting their role in autism genetics.

Implications and Future Directions

These findings provide a framework for understanding how diverse genetic mutations contribute to autism. The study suggests that manipulating long noncoding RNAs could potentially restore lost gene function, offering a new therapeutic avenue. Future research will integrate these findings with studies using brain organoids to explore how different cell types are affected by genetic disruptions.

Rebecca Andersen notes, “We’re finding this really interesting signal of autism-associated genes that are changing when we perturb just a single autism-associated gene.” This research underscores the complexity of autism genetics and highlights the potential for targeted interventions based on a deeper understanding of these genetic networks.

The study by Walsh’s lab demonstrates the power of modern genetic techniques in unraveling the complex genetic underpinnings of autism. By exploring how different genes interact within a network, researchers can better understand how disruptions in these genes lead to similar neurodevelopmental outcomes. This work not only advances our understanding of autism but also opens new paths for potential therapeutic interventions.

While specific citations are not provided in the original text, this research aligns with broader efforts in autism genetics, such as those by Evan Eichler, who has contributed significantly to understanding the role of chromatin remodeling in autism.

Citations:

1. https://www.thetransmitter.org/spectrum/sequencing-study-spotlights-tight-web-of-genes-tied-to-autism/
2. https://www.biorxiv.org/content/10.1101/2025.01.17.633619.full.pdf
3. https://www.hhmi.org/news/autism-gene-screen-highlights-protein-network
4. https://www.biorxiv.org/content/10.1101/2025.01.20.634000v1.full.pdf
5. https://www.sciencedaily.com/releases/2012/04/120404133656.htm
6. https://www.washington.edu/news/2012/04/04/autism-mutations-scattered-across-genes-merge-into-network-of-interactions/
7. https://www.biorxiv.org/content/10.1101/2025.01.17.633619v1.full-text
8. https://www.biorxiv.org/content/biorxiv/early/2025/01/22/2025.01.20.634000.source.xml
9. https://www.medrxiv.org/content/10.1101/2023.09.19.23295780v1
10. https://www.biorxiv.org/content/10.1101/2024.06.05.597673v2.full.pdf
11. https://www.biorxiv.org/content/10.1101/2020.02.11.944413.full
12. https://www.biorxiv.org/content/biorxiv/early/2023/12/04/2023.12.03.569805.full.pdf
13. https://www.biorxiv.org/content/10.1101/2020.11.15.375386v1.article-info
14. https://www.biorxiv.org/content/10.1101/2025.01.20.634000v1
15. https://www.biorxiv.org/content/10.1101/2024.08.14.608000v1.full.pdf
16. https://pmc.ncbi.nlm.nih.gov/articles/PMC7983596/
17. https://walshlab.org/publications/
18. https://pubmed.ncbi.nlm.nih.gov/39896631/
19. https://www.nimh.nih.gov/news/science-updates/2012/spontaneous-gene-glitches-linked-to-autism-risk-with-older-dads
20. https://alliance-uoregon.primo.exlibrisgroup.com/discovery/fulldisplay?docid=cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3350576&context=PC&vid=01ALLIANCE_UO%3AUO&lang=en&adaptor=Primo+Central&tab=Rollup&query=null%2C%2C272%2CAND&facet=citing%2Cexact%2Ccdi_FETCH-LOGICAL-c714t-cc37943b9ae93f7ffcf5d30fd75545b7100efc5a294d30b8db4e1a0758437ce3&offset=0
21. https://www.nature.com/articles/ng0412-471
22. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000482.v1.p1
23. https://www.nytimes.com/2012/04/05/health/research/scientists-link-rare-gene-mutations-to-heightened-risk-of-autism.html
24. https://pure.psu.edu/en/publications/sporadic-autism-exomes-reveal-a-highly-interconnected-protein-net
25. https://europepmc.org/article/med/22495309
26. https://na01.alma.exlibrisgroup.com/discovery/fulldisplay?docid=cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3350576&context=PC&vid=TR_INTEGRATION_INST%3ADEFAULT&lang=en&search_scope=MyInst_and_CI&adaptor=Primo+Central&query=null%2C%2CBMC%2CAND&facet=citing%2Cexact%2Ccdi_FETCH-LOGICAL-c464t-d44b8552fe07c9c8b8814928de51f977428fa12225ba89ba0428786918bbb0c03&offset=0
27. https://www.nature.com/articles/ng.2516
28. https://www.nature.com/subjects/autism-spectrum-disorders/ng
29. https://www.nature.com/articles/nrneurol.2012.82
30. https://www.sfari.org/people/christopher-walsh/
31. https://www.biorxiv.org/content/10.1101/484113v3
32. https://research.childrenshospital.org/researchers/christopher-walsh
33. https://www.biorxiv.org/content/10.1101/2024.12.05.626924v3.full-text
34. https://www.biorxiv.org/content/10.1101/2024.12.05.626924v3.full.pdf
35. https://www.nature.com/articles/ncomms5954
36. https://www.thetransmitter.org/spectrum/questions-evan-eichler-evolving-theory-autism/
37. https://www.nimh.nih.gov/news/science-news/2012/spontaneous-gene-glitches-linked-to-autism-risk-with-older-dads
38. https://pubmed.ncbi.nlm.nih.gov/22495309/