New research has uncovered how specific genetic variations determine whether individuals are more likely to develop autism-like traits or psychosis, offering new insights into the genetic roots of major psychiatric disorders. A comprehensive review by scientists at the University of Haifa, published in the journal Genomic Psychiatry, shows that the type of genetic alteration causing Prader-Willi syndrome (PWS)—a rare genetic condition—has a major impact on the likelihood of psychiatric symptoms.
According to the study, individuals with a deletion on chromosome 15 inherited from their father are more prone to autism-related behaviors, while those with two maternal copies of the chromosome—a condition called maternal uniparental disomy (mUPD)—are at significantly higher risk of developing psychosis during adolescence or adulthood.
GENETIC IMPRINTING: GENE’S PARENT OF ORIGIN MATTERS
Unlike most genes that function regardless of which parent they come from, some genes are “imprinted”—meaning they are only active when inherited from a specific parent. In Prader-Willi syndrome (PWS), critical genes on chromosome 15 are typically expressed only from the father’s copy. When this paternal genetic material is missing or disrupted, it can lead to abnormal brain development and increase the risk of psychiatric conditions, depending on the nature of the genetic defect.
“This syndrome provides a rare window into how precise genetic changes can shape the human brain,” said Professor Shani Stern, lead author of a new review. “The insights we gain here may help us understand broader patterns in mental health across the population.”
PWS is a rare genetic disorder—occurring in roughly one out of every 16,000 to 76,000 births—that arises from problems with gene expression in a specific region of chromosome 15. The disorder is particularly valuable to psychiatric researchers because different forms of the condition are associated with different mental health profiles. For example, people with a deletion of the paternal segment of chromosome 15 are more likely to exhibit traits associated with autism, while those with two maternal copies of the chromosome (a condition known as maternal uniparental disomy) have a higher risk of developing psychosis later in life.
In their comprehensive review, Professor Stern from the University of Haifa’s Department of Neurobiology and Professor Ahmed Abu-Akel from the School of Psychological Sciences analyzed findings from dozens of studies that explored how these genetic subtypes of PWS influence psychiatric outcomes. Previous research has shown that 12% to 40% of individuals with PWS exhibit autism-like behaviors, and 10% to 30% may experience psychotic symptoms in adolescence or adulthood.
The review integrated research from multiple fields—molecular genetics, neuroimaging, and cellular biology—to understand the relationship between specific genetic alterations and changes in brain structure and function. The authors focused on three key genetic causes of PWS: paternal deletions, maternal disomy, and defects in the imprinting mechanisms that regulate gene activity. They examined brain imaging studies that showed how these different genetic types affect brain structure and connectivity and also looked at lab-based research using patient-derived stem cells, which were used to grow nerve cells and study their development and function in controlled settings.
The findings reveal that each genetic subtype of PWS is associated with distinct patterns in the brain. Individuals with a paternal deletion typically show reduced volume in brain areas responsible for regulating behavior and emotions, such as the prefrontal cortex and cerebellum. Meanwhile, those with maternal disomy tend to have abnormal connectivity in regions related to emotion and social perception—patterns that resemble those found in schizophrenia.
On a cellular level, the research found that neurons derived from PWS patient stem cells exhibited variations in synaptic function, neural signaling, and drug responsiveness depending on the underlying genetic cause. These differences could help explain why psychiatric symptoms in PWS vary so widely—and why tailored treatments may be more effective than one-size-fits-all approaches.
“The genetic differences in PWS give us a biological framework for understanding how genes influence brain development and mental health,” said the researchers. “Small variations in genetic code can trigger very different developmental paths and psychiatric risks.”
Beyond offering new insights into PWS, the study suggests that these findings could inform a broader shift toward personalized psychiatry—where treatments are guided by a patient’s specific genetic and neurological profile. Understanding how certain genetic mutations alter brain function may help researchers develop more precise diagnostic tools and interventions, and even anticipate psychiatric symptoms before they arise.
“We are just beginning to grasp how genetic information is transformed into brain structure and behavior,” said Professor Stern. “Prader-Willi syndrome gives us a unique opportunity to map that transformation—and with it, the potential to rethink how we approach mental illness.”
