Researchers at UCLA and the University of Pittsburgh have gained insight regarding the genetic basis of autism spectrum disorder and psychosis. The findings of their new study could lead to new diagnostic methods that could lead to early interventions that could significantly improve the quality of life of affected individuals. The findings were published online in PLOS One on July 24.
The study authors note that it is well-known that children who are missing about 60 genes on a certain chromosome are at a significantly increased risk for developing either an autism spectrum disorder or psychosis (any mental disorder characterized by delusions and hallucinations, including schizophrenia). However, no method exists regarding how to predict which child with the abnormality might be at risk for which disorder. The new study suggests such a method. The researchers have isolated specific genetic differences between individuals with the chromosomal deletion, known as 22q11.2 deletion syndrome or DiGeorge syndrome, who have autism and those who have psychosis.
“Ultimately, this kind of information could be used as a diagnostic tool that could allow pediatricians or other clinicians to determine who will develop which disorder, so that the appropriate intervention can be applied, and applied early enough to have the most impact,” explained senior author Carrie Bearden, PhD, a professor of psychiatry and psychology at UCLA. She added, “We know that early intervention is very important for people at risk for autism or psychosis.”
DiGeorge syndrome affects approximately 1 in 2500 children born worldwide, and is the second most common chromosomal abnormality, after Down syndrome. It can be detected with an amniocentesis, which entails drawing a sample of amniotic fluid for genetic analysis. Children with the syndrome usually have elongated faces, almond-shaped eyes, and unusual outer ears. In addition, they frequently have palate abnormalities, including cleft palate, and they are at elevated risk for cardiovascular defects.
DiGeorge syndrome is the highest known genetic risk factor for psychosis; furthermore, it is one of many known genetic risk factors for autism. Approximately30-40% of individuals with the syndrome are diagnosed with an autism spectrum disorder, and 25-30% are diagnosed with a psychotic disorder. (A small number of indivdulas with the syndromeare diagnosed with both autism and psychosis.)
“The hope is that eventually we could identify individuals at risk for either disorder with a blood sample,” rxplained lead author Maria Jalbrzikowski, who was a postdoctoral fellow in Dr. Bearden’s lab while they were conducting the study. Jalbrzikowski is now a postdoctoral fellow at the University of Pittsburgh. For the study, the researchers drew blood samples from 46 UCLA patients with the deletion and also took blood samples from 66 control subjects. They analyzed the samples via a new technique developed by UCLA geneticist Steve Horvath. Called “weighted gene co-expression network analysis,” it allows scientists to search for patterns of genes that are connected to one another. The analysis determined whether specific gene expression patterns, i.e., whether specific groups of genes are activated for a given trait, were associated with psychosis or autism.
On average, individuals with DiGeorge syndrome and psychosis had 237 genes that showed a different pattern from the genes of people with the syndrome but without psychosis. Most of these genes were associated with the regulation of gene expression (the degree that a specific gene affects a particular trait.
“Having one chunk of DNA missing appears to cause downstream effects, with other functions becoming disrupted,” explained Dr. Bearden. In a separate step, the investigators compared the genes associated with psychosis in the UCLA group of DiGeorge syndrome patients with psychosis to those of a sample of 180 Dutch patients who had been diagnosed with schizophrenia but did not have the syndrome. They discovered an overlap of seven genes. “This finding is really important because it provides proof that altered gene expression patterns in those with DiGeorge syndrome and psychosis are shared with people who are diagnosed with schizophrenia but do not have the deletion,” noted Dr. Bearden. She added, “The same pathways are affected.” She added that the seven overlapping genes play a role in fetal brain development, suggesting that psychosis may originate during the early stages of brain development.
The researchers also found that patients with DiGeorge syndrome and autism differed from their counterparts without autism in the expression of 86 genes, which are likely involved in the development of the immune system. The authors believe that their study is the first attempt at understanding the genetic differences between DiGeorge syndrome patients with autism and those with psychosis.
The research team is planning a future study that will attempt to replicate their findings in larger groups of patients and in other cell types (such a brain tissue) in patients with DiGeorge syndrome. The approach they used, weighted gene co-expression network analysis, also holds promise for research on individuals missing genes on chromosomes 15 and 16,. Those individuals also are at a higher-than-normal risk of psychotic disorders, intellectual disability and epilepsy.