Research Uncovers Genetic Variant Underlying Schizophrenia

Excessive activity in complement component 4 (C4) genes linked to the development of schizophrenia may explain the excessive pruning and reduced number of synapses in the brains of patients with schizophrenia, according to a study published in Nature.

The study, co-funded by the Office of Genomics Research Coordination at the National Institute of Mental Health and the Stanley Center for Psychiatric Research at the Broad Institute in Cambridge, Massachusetts, analyzed various structurally diverse versions of the C4 gene.

Led by Steve McCarroll, PhD, of the Broad Institute of Harvard and MIT, researchers analyzed the genomes of 65 000 study participants and 700 postmortem brains, detecting a link between specific gene versions and the biological process that causes some cases of schizophrenia.

The team—including Beth Stevens, PhD; Michael Carroll, PhD; and Aswin Sekar, BBS— determined that C4 genes generate varying levels of C4A and C4B proteins; the more C4A found in a person, the higher his or her risk of developing schizophrenia.  The researchers found that during critical periods of brain maturation, C4 identifies synapses for pruning. Overexpression of C4 results in higher amounts of C4A, which could cause excessive pruning during the late teens and early adulthood, “conspicuously corresponding to the age-of-onset of schizophrenia symptoms,” the researchers noted.

“It has been virtually impossible to model [schizophrenic] disorder in cells or animals,” said Dr McCarroll. “The human genome is providing a powerful new way into this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.”

Research suggests that future schizophrenia treatments may be developed to target and suppress excessive levels of pruning, halting a process that has the potential to develop into psychotic illness.

Reference

Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; doi: 10.1038/nature16549.