UCSF QBI Creates Largest Ever Molecular Map of Autism, Opening New Paths to Precision Therapies

—Landmark study published in Science maps over 1,800 protein interactions across 100 autism risk genes, revealing how diverse genetic mutations converge on shared molecular pathways and establishing a novel blueprint for translating genetics into therapies—

SAN FRANCISCO--(BUSINESS WIRE)--For more than two decades, researchers have identified hundreds of genes that increase the risk of autism spectrum disorder (ASD). Yet multiple fundamental questions have remained unanswered: among them, how do mutations in these genes lead directly to changes in brain development and how can that knowledge be translated into more effective therapies?

In a landmark study published today in Science, scientists at the Quantitative Biosciences Institute (QBI) and the Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco (UCSF) have taken a major step toward answering both questions. The findings are the result of more than a decade of work. By building the largest-ever molecular interaction map of autism, the team revealed how hundreds of genes and dozens of mutations converge within a surprisingly small number of shared protein networks, hurdling a major roadblock to the development of new precision medicines.

Rather than focusing only on the genes linked to autism, the researchers mapped the proteins encoded by those genes and discovered exactly how individual disease-causing mutations can rewire the molecular machinery of the developing brain. The work uncovers an entirely new layer of disease biology that can be targeted therapeutically and provides a framework for designing medicines that directly address a wide range of underlying molecular causes of autism.

Perhaps the study's most important discovery is that many genetically distinct forms of autism converge on disrupting the same protein complexes. Instead of requiring a different therapy for every mutation, these shared molecular hubs could enable the development of medicines capable of treating multiple genetic forms of autism simultaneously. Compared to gene-targeting approaches such as antisense oligonucleotides (ASOs) or CRISPR-based therapies, drugs designed to restore these shared protein interactions could potentially benefit many patients while offering advantages in brain delivery, tolerability, scalability, and manufacturing.

The study is most directly relevant to the approximately 30% of individuals with profound autism, many of whom carry rare, high-impact mutations in established autism risk genes. More broadly, it establishes a general framework for connecting disease-causing genetic variation to protein networks, molecular mechanisms, and therapeutic targets, a strategy that may ultimately be applicable across many human diseases.

The study, led by co-first authors Belinda Wang, M.D., Ph.D., Rasika Vartak, Ph.D., and Kelsey Hennick, Ph.D., along with co-corresponding authors Kirsten Obernier, Ph.D., Tomasz J. Nowakowski, Ph.D., and A. Jeremy Willsey, Ph.D., and published in Science on August 27, 2026, systematically mapped protein-protein interactions for 100 high-confidence autism risk genes using affinity purification-mass spectrometry (AP-MS), identifying more than 1,800 protein interactions, 87% of which had never been reported previously. The researchers then analyzed 54 patient-derived autism mutations, revealing how distinct genetic variants rewire protein interaction networks to produce convergent effects on brain development.

“After the initial excitement of discovering rare mutations that cause common forms of autism, the reality of how hard it would be to develop medicines to target the most severe end of the autism spectrum became abundantly clear,” said Matthew W. State, M.D., Ph.D., a senior author and Chair of the Department of Psychiatry and Behavioral Sciences at UCSF. “This current work opens up a whole new world of possibilities for therapeutic targets and promises a generation of novel drugs that can transform what we are able to do in the clinic.”

“The science demonstrates that autism is written in our genes," stated Nevan J. Krogan, Ph.D., professor at UCSF, director of QBI, and senior investigator at Gladstone Institutes. "This study maps the exact molecular machinery that is altered, including the specific protein interactions, down to the interfaces we can target with a drug. Further, what we've built here isn't limited to autism. It's a blueprint for translating the genetics of almost any disease from neurodegeneration to cancer, into a real therapeutic strategy. That's what we've been building QBI to do."

Key Study Findings:

• Largest molecular interaction map ever generated for autism. The study focused on 100 autism risk genes and mapped over 1,800 protein-protein interactions, with 87% of those interactions were previously unknown. The study is the most detailed “diagram” ever created for the molecular machinery underlying autism, revealing connections between proteins that were previously invisible.
• Autism’s genetic diversity funnels into a small number of shared molecular pathways. Even though autism can be caused by hundreds of different genes, the relevant changes in those genes, the mutations that cause many cases of autism, tend to alter a much smaller number of shared protein complexes. This discovery implies that researchers may be able to develop therapies that target common molecular hubs rather than needing a different drug for every mutation. This new finding has the potential to dramatically accelerate new therapies and improve benefits for patients.
• Disease-causing mutations don’t just break genes, they rewire protein networks in predictable, convergent ways. Distinct mutations in different autism genes produce surprisingly similar changes in how proteins interact with each other. For example, separate autism-causing mutations in the gene FOXP1 and FOXP2 converge on disrupting the same FOXP1-FOXP4 protein interaction, leading to premature development of cortical neurons and increased neural circuit excitability in lab-grown brain organoids.
• AI reveals precisely where disease-causing mutations act. By integrating the interaction maps with AlphaFold structural predictions, researchers pinpointed where mutations disrupt protein interfaces, creating opportunities to design drugs that stabilize beneficial interactions or block harmful ones.
• A new layer of disease biology: Mutations that cause a gain of harmful function, not just a loss. In one example, FOXP1 mutations that sit at entirely different locations within the protein all converge on disrupting the same FOXP1-FOXP4 interaction. Rather than simply reducing the amount of FOXP1, a mechanism that has been presumed to be the primary means by which large effect ASD mutations cause the syndrome, the genetic changes in FOXP1 trigger a pathogenic gain of function in the partner protein FOXP4. This unexpected finding reveals a new dimension of how autism mutations can cause harm, and opens new avenues for therapeutic intervention. 
• A blueprint for the future of precision medicine. Beyond autism, the framework developed in this study, connecting genetic mutations to protein interaction networks to disease mechanisms to therapeutic targets, represents a new model for how to translate the genetics of any disease into a treatment strategy. QBI’s PPI platform is now positioned to apply this approach across neurology, oncology, and infectious diseases.

QBI's landmark mapping of the SARS-CoV-2 human protein interaction network during the COVID-19 pandemic identified 69 drug candidates, 27 of which advanced into clinical trials. The study also represents a critical milestone in a more than decade-long partnership between QBI and the Department of Psychiatry and Behavioral Sciences at UCSF, known as the Psychiatric Cell Map Initiative (PCM; https://pcmi.ucsf.edu/). This effort has identified the causal biology of a neuropsychiatric disorder at the molecular level, laid the foundation for a targeted therapeutic approach in autism spectrum disorder, and established a generalizable blueprint for going from genetics to therapy that could transform how we approach any complex genetic disease.

ABOUT THE QUANTITATIVE BIOSCIENCES INSTITUTE (QBI)

The Quantitative Biosciences Institute (QBI) is a University of California organized research unit reporting through the UCSF School of Pharmacy. QBI fosters collaborations across the biomedical and physical sciences to advance interdisciplinary approaches to human disease and therapeutic discovery. QBI’s disease-agnostic, uniquely integrated technological platforms have generated insights across cancer, neurodegeneration, and infectious diseases, leading to the formation of spinout companies, including Rezo Therapeutics. QBI incorporates the UCSF division of QB3, a multicampus UC institute that supports bioscience research and innovation in California. Learn more at qbi.ucsf.edu.

ABOUT THE UCSF DEPARTMENT OF PSYCHIATRY AND BEHAVIORAL SCIENCES

The UCSF Department of Psychiatry and Behavioral Sciences and the Langley Porter Psychiatric Institute are among the nation's foremost resources in the fields of child, adolescent, adult, and geriatric mental health. Together they constitute one of the largest departments in the UCSF School of Medicine and the UCSF Weill Institute for Neurosciences, with a focus on providing unparalleled patient care, conducting impactful research, training the next generation of behavioral health leaders, and expanding access, awareness, and advocacy across the field of behavioral health. Learn more at psychiatry.ucsf.edu.