UW study identifies genetic changes tied to more severe cognitive symptoms in schizophrenia
Our take
This latest research from the University of Washington, identifying genetic changes linked to more severe cognitive symptoms in schizophrenia, represents a significant step forward in our understanding of this complex disorder. It aligns with a growing body of evidence suggesting that genetic factors play a crucial role in not only the presence of schizophrenia, but also the *severity* of its manifestations. The focus on deletions within genes regulating early brain development is particularly noteworthy—it suggests that disruptions occurring very early in life can have lasting and profound impacts, shaping the trajectory of cognitive function. This builds upon previous research, and connects nicely to work being done in areas like accelerated drug discovery, as seen in [Q&A: How UW researchers are using AI to speed up drug discovery and development]. Understanding these underlying genetic mechanisms is foundational to developing more targeted and effective interventions, moving beyond current symptom management strategies.
The implications of this study extend beyond purely academic interest. Schizophrenia is a devastating illness, often characterized by significant cognitive deficits that impact daily functioning, independence, and quality of life. While antipsychotic medications can help manage positive symptoms like hallucinations and delusions, they often have limited impact on negative symptoms (such as social withdrawal and lack of motivation) and cognitive impairments. Identifying specific genetic vulnerabilities opens avenues for earlier diagnosis—potentially through genetic screening—and for developing personalized treatment approaches that address the unique biological underpinnings of each individual’s condition. The development of new delivery methods for medications, highlighted in [Q&A: How UW researchers are using AI to speed up drug discovery and development], could further revolutionize treatment possibilities by allowing for more targeted delivery of therapies to the affected brain regions. This is especially relevant considering the challenges in ensuring consistent medication adherence among individuals with schizophrenia.
Furthermore, the meticulous focus on cognitive abilities as an outcome measure is important. Historically, schizophrenia research has often centered on “positive” symptoms, overlooking the significant burden imposed by cognitive deficits. This study’s emphasis on cognitive function acknowledges that these impairments are a central component of the disorder and contribute substantially to disability and impaired social functioning. The study’s findings are also consistent with the broader effort to unravel the complex interplay between genetics, environment, and brain development in mental illness. It reinforces the idea that schizophrenia isn’t a single entity, but rather a spectrum of disorders with varying underlying causes and clinical presentations. Research continuing in fields like drug development, as mentioned in [Q&A: How UW researchers are using AI to speed up drug discovery and development], will be crucial in translating these genetic insights into tangible therapeutic advancements.
Looking ahead, a crucial question is whether we can leverage this understanding of genetic vulnerabilities to develop preventative interventions. Could early identification of individuals at high risk, coupled with targeted interventions designed to support healthy brain development, mitigate the severity of schizophrenia symptoms? The challenge lies in identifying practical and ethical ways to implement such preventative strategies. More research is needed to understand the precise mechanisms by which these genetic deletions impact brain function, and to explore the potential for gene therapies or other innovative treatments that could correct these underlying abnormalities. The pace of progress in genomics and neuroscience offers real hope for improving the lives of individuals and families affected by schizophrenia, but careful consideration of ethical and societal implications will be paramount.
Schizophrenia affects approximately 23 million people worldwide, with onset usually occurring during a person’s late adolescence to their 20s. Impairments associated with schizophrenia include hallucinations, delusions and disorganized thinking and behavior.
Now, researchers at the University of Washington are investigating how genetic changes impact the severity of schizophrenia symptoms. A new study, published in the American Journal of Psychiatry, supports the idea that deletions in genes that regulate early brain and neuron development are associated with more severe features of schizophrenia spectrum disorders, particularly lower cognitive abilities.
How schizophrenia manifests — and how severely — differs between patients. Poorer cognitive functioning in schizophrenia is associated with more treatment-resistant forms of the disease. Jennifer Forsyth, co-author and assistant professor of psychology at the UW, said understanding early developmental genetic factors could help identify people who could benefit from earlier, targeted inventions.
“For a subset of individuals, we may need to be thinking about how we can create treatments earlier in brain development that will help compensate for the fact that certain genes are being deleted,” Forsyth said. “Is there some kind of medication that can help with that? Down the road, could there be gene therapies for some of these individuals? I do think this research is going to be important for changing treatment direction.”
The researchers studied the DNA of more than 600 people with schizophrenia spectrum disorders. The team compared these results to data from patients’ relatives, people without schizophrenia and nearly 10,000 children participating in the Adolescent Brain Cognitive Development Study.
People with schizophrenia who carried the deletions tended to perform worse on cognitive tests — showing poorer memory, thinking and attention skills than people with schizophrenia who didn’t carry the deletions. Similar, weaker associations were also seen in the general population, which suggests these variants may influence brain development more broadly, even in individuals without schizophrenia.
The study also showed these specific genetic deletions were associated with differences in brain structure, including higher gray matter volume and cortical thickness. This is the opposite pattern researchers typically see on average in schizophrenia, Forsyth said, which again suggests variability between patients.
“This study helps us understand the specific way somebody manifests a disorder,” Forsyth said. “It’s sort of a cumulative effect of different risk profiles. We all carry tons of genetic variants, and the specific types of variants we have and how they combine is very complicated. These things aren’t totally deterministic, but I do think understanding which specific aspects of brain development are affected by the genetic variants a person carries, and how this shapes how the disorder manifests, can start to inform how we think about different treatment approaches.”
Other UW co-authors from the Department of Psychology were graduate students Jinhan Zhu, Zachary Trevorrow and Mahnoor Hyat, undergraduate research assistant Ariana Chavannes, research coordinator Sam Sievertsen and research technologist Sophie Ferreira-Ianone. Matthew Conomos, a UW senior research scientist in biostatistics, was also a co-author.
A full list of co-authors is included with the study.
This study was funded by the National Institute of Mental Health, the Brain and Behavior Research Foundation, the National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute, the UCLA Brain Research Institute and the Shear Family Foundation.
For more information, contact Forsyth at jenforsy@uw.edu.
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