Researchers at the University of Washington are investigating how genetic changes impact the severity of schizophrenia symptoms. How schizophrenia manifests — and how severely — differs between patients.
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Scientific Frontline: Extended "At a Glance" Summary: Genetic Deletions and Schizophrenia Severity
The Core Concept: Deletions in genes that regulate early brain and neuron development are associated with more severe features of schizophrenia spectrum disorders, specifically diminished cognitive abilities.
Key Distinction/Mechanism: While schizophrenia is typically associated with reduced brain tissue, patients with these specific genetic deletions paradoxically exhibit higher gray matter volume and greater cortical thickness, demonstrating distinct biological variability in how the disorder manifests.
Major Frameworks/Components:
- Genetic variant profiling to assess the cumulative effect of early developmental genetic risk factors.
- Neuroanatomical structural analysis focusing on gray matter volume and cortical thickness.
- Cognitive performance metrics assessing memory, abstract thinking, and attention skills.
Branch of Science: Neurogenetics, Psychiatry, Neuroscience, and Evolutionary Biology.
Future Application: The identification of these variants paves the way for early, targeted clinical interventions during brain development, including compensatory medications and potential localized gene therapies for treatment-resistant forms of the disease.
Why It Matters: Understanding how specific genetic variants dictate early brain development and shape the disorder's severity allows researchers to move away from uniform diagnostic interventions and toward highly individualized, personalized psychiatric treatment approaches.
Schizophrenia affects approximately 23 million people worldwide, with onset usually occurring during a person’s late adolescence or their twenties. 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, coauthor and assistant professor of psychology at the University of Washington, said understanding early developmental genetic factors could help identify people who could benefit from earlier, targeted interventions.
“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 did not 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.”
Funding: 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.
Published in journal: American Journal of Psychiatry
Authors: Jennifer K. Forsyth, Ph.D., Jinhan Zhu, M.Sc., Ariana S. Chavannes, B.A., Zachary H. Trevorrow, M.A., Mahnoor Hyat, M.A., Sam A. Sievertsen, B.A., Sophie Ferreira-Ianone, B.Sc., Matthew P. Conomos, Ph.D., Keith H. Nuechterlein, Ph.D., Robert F. Asarnow, Ph.D., Michael F. Green, Ph.D., Katherine H. Karlsgodt, Ph.D., Diana O. Perkins, M.D., M.P.H., Tyrone D. Cannon, Ph.D., Jean M. Addington, Ph.D., Kristen S. Cadenhead, M.D., Barbara A. Cornblatt, Ph.D., Matcheri S. Keshavan, M.D., Daniel H. Mathalon, M.D., Ph.D., William S. Stone, Ph.D., Ming T. Tsuang, M.D., Ph.D., Elaine F. Walker, Ph.D., Scott W. Woods, M.D., Katherine L. Narr, Ph.D., Sarah C. McEwen, Ph.D., Charles H. Schleifer, Ph.D., Cindy M. Yee, Ph.D., Caroline K. Diehl, Ph.D., Anika Guha, Ph.D., Gregory A. Miller, Ph.D., Aaron F. Alexander-Bloch, M.D., Ph.D., Zhiqiang Sha, Ph.D., Joseph Glessner, Ph.D., Jakob Seidlitz, Ph.D., Richard A. I. Bethlehem, Ph.D., Roel A. Ophoff, Ph.D., and Carrie E. Bearden, Ph.D.
Source/Credit: University of Washington | Lauren Kirschman
Edited by: Scientific Frontline
Reference Number: psyc072826_01
