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The gene, known as complement component 4 (C4), acts as part of a system that destroys foreign invaders such as bacteria and removes the resulting debris from cells. The complement system also works to remove excess connections between nerve cells as the brain matures.
“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, Ph.D., director of the Office of Genomics Research Coordination at the National Institute of Mental Health (NIMH), said in a news release. “[This] 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.” NIMH co-funded this study.
In 2014, a landmark NIMH-led genomics study uncovered over 80 new risk variants for schizophrenia. A variant identified on chromosome 6 produced by far the strongest degree of risk, but it has been difficult for researchers to determine the specific genes accounting for this increased risk.
In the current study, Steven McCarroll, Ph.D., and colleagues analyzed the genomes of nearly 65,000 people, with or without schizophrenia, and found C4 appears to increase a person’s risk of schizophrenia. Additional analysis in a mouse model revealed that the more C4 activity, the greater the removal of neuronal connections, which may help to explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
“Differential synaptic pruning has been a longstanding hypothesis for decades, first put forward by Irwin Feinberg in the 1980s,” said William Carpenter, M.D., a professor of psychiatry at the University of Maryland School of Medicine. “It's been very difficult to prove it one way or the other, but these new findings do point directly to a potential mechanism.
For related information, see the Psychiatric News article “Study Identifies Factors Predictive of Response to Risperidone.”
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