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NIH study explores genetic risk for schizophrenia

Versions of a gene associated with schizophrenia may prompt synaptic pruning during adolescence, according to recent findings from an NIH-funded study.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” Thomas Lehner, PhD, director of the Office of Genomics Research Coordination at the NIMH, said in a press release. “It could help explain schizophrenia's delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain's working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

To investigate the most well-known genetic risk for schizophrenia, researchers analyzed genomes from 65,000 individuals and 700 postmortem brain samples with mouse genetic engineering.

Genome-wide analyses indicated that chromosome 6, which includes several genes known to be associated with immune function, was most significantly associated with schizophrenia risk.

To determine how the immune-related region confers risk for schizophrenia, researchers looked for subtle genetic influences that may produce unconventional signs.

They considered complement component 4 (C4), which has a known role in immunity and is unusually variable across individuals.

Bruce Cuthbert

Analysis indicated structurally distinct versions that affected expression of the two main gene forms in the brain.

One of the expressions, C4A, was associated with increasing schizophrenia risk.

Further, risk for schizophrenia increased as the number of suspect versions of C4 and the expression of C4 increased.

Using mouse molecular genetic techniques to study synaptic pruning and C4, researchers found that C4 indicates a synapse for pruning by depositing a sister protein in it (C3) during critical periods of postnatal brain development.

“This study marks a crucial turning point in the fight against mental illness. It changes the game," Bruce Cuthbert, PhD, acting director of the NIMH, said in the release. “Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments and even prevention.” – by Amanda Oldt

Disclosure: The researchers report no relevant financial disclosures.