Genetic deletions may help explain differences in schizophrenia severity

Schizophrenia affects approximately 23 million people worldwide, with onset usually occurring during a person’s late adolescence or 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 affect 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.

Clues to more severe cases

How schizophrenia manifests—and how severely—differs among 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 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.”

Comparing DNA across groups

The researchers studied the DNA of more than 600 people with schizophrenia spectrum disorders. The team compared these results with 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 but weaker associations were also seen in the general population, suggesting these variants may influence brain development more broadly, even in individuals without schizophrenia.

An unexpected brain pattern

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, again suggesting variability among 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 are 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.

Who’s behind this story?

Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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