Structural gene mutations disrupt neurodevelopment in schizophrenia

MedWire News: Patients with schizophrenia carry rare structural gene mutations that impact upon neurodevelopment pathways and may contribute to overall disease phenotype, say US researchers.

The team found that schizophrenia patients showed a higher rate of novel gene microduplications and microdeletions than age-matched mentally healthy controls.

Tom Walsh (University of Washington, Seattle) and colleagues say their findings call for "a new approach to gene discovery" in schizophrenia and other psychiatric disorders and may explain why previous attempts to find genetic causes for such illnesses have not been fruitful.

"Neurodevelopment pathways involve hundreds of genes... a severe mutation in any one of these genes may lead to a psychopathological phenotype," say Walsh et al in the journal Science.

They add: "Although each mutation may be individually rare, collectively the total number of disease-causing variants in a gene relevant to the disorder may explain a substantial number of cases."

Previous studies have identified large-scale chromosomal abnormalities, such as deletions at 22q11.2, which are associated with schizophrenia symptoms; however, these karyotype studies are unable to detect smaller deletions.

In the present study, the researchers used a technique called comparative genomic hybridization to identify gene breakpoints in 150 patients with schizophrenia and 268 mentally healthy controls.

Initial analysis revealed 115 commonly occurring microduplications and microdeletions, ranging from 100kb to 15 MB, which were present at a frequency of more than 1% in the study sample. The occurrence of these common variants did not differ significantly between cases and controls.

The researchers then identified 53 previously unreported structural variants that were present at a frequency of much less than 1%, with most mutations occurring only once in a single individual. Patients with schizophrenia were more than three times more likely to harbor these rare structural variants than mentally healthy controls, while patients who presented with symptoms before the age of 18 years were nearly five times more likely to carry them.

Further analysis revealed that many of the microduplications and microdeletions occurring in schizophrenia patients affected pathways important for brain development, including neuregulin signaling, extracellular signal-regulated kinase /mitogen-activated protein kinase signaling, synaptic long-term potentiation, axonal guidance signaling, integrin signaling, and glutamate receptor signaling.

Walsh and colleagues conclude by saying that prevention strategies should be "tailored towards the remediation of the altered pathways."