A biological mechanism for schizophrenia

Researchers had previously linked more than 100 genetic regions to schizophrenia risk, but the underlying disease mechanisms remained unknown. kirstypargeter/iStock/Thinkstock

Schizophrenia is a chronic, severe mental disorder that affects how a person thinks, feels, and behaves. It can cause hallucinations, delusions, and other mental problems that make it seem like a person has lost touch with reality. It affects about 1 in 100 people.

Several factors likely contribute to the risk of developing schizophrenia. It tends to run in families, so much research has focused on genetic variations that affect disease risk. Past genome-wide analyses have linked more than 100 genetic regions to schizophrenia risk. However, the specific genes and sequences that confer risk remained largely unknown.

A team of scientists led by Dr. Steve McCarroll of the Broad Institute and Harvard Medical School examined the region with the strongest link to schizophrenia risk. They noted associations near the C4 gene, which encodes for complement component 4. C4 is part of the complement cascade, an immune system pathway that eliminates pathogens and cellular debris. Their investigation, which was funded by several NIH components, was published online on January 27, 2016, in Nature.

Human C4 exists in 2 forms, C4A and C4B. The protein products from these genes vary in structure and in their molecular targets. Both genes can also vary in length as well as in the number of genomic copies. The researchers first developed a way to distinguish these different forms. When they measured RNA levels in post-mortem human adult brain samples, they found that the different forms predicted C4A and C4B expression levels in the brain.

The team next analyzed the genomic variations of nearly 65,000 people (29,000 with schizophrenia) in this region and predicted the different forms of C4 and their expression levels. They discovered that the more strongly a variation correlated with the predicted expression of C4A, the more strongly it associated with schizophrenia.

The scientists compared expression levels in brain tissue from schizophrenia patients and controls. Both genes were expressed at higher levels in brain tissues from schizophrenia patients, but expression levels of C4A were 2-3 times greater than levels of C4B. Analysis of both human brain tissue and neurons in the lab confirmed C4 production in neurons, particularly at sites of connection between neurons, called synapses.

These findings, along with evidence from other studies, suggested to the researchers that C4 might work with other components of the classical complement cascade to promote synaptic pruning. In humans, this process occurs as the brain develops to full maturity, in the late teens to early adulthood. This period is also often when schizophrenia symptoms begin.

To test this hypothesis, the researchers used a mouse model to examine C4 function during development. They found that C4 tags a synapse for pruning via another protein called C3. The higher the levels of C4 in the mice, the greater the synaptic pruning.

“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,” says Dr. Thomas Lehner of NIH’s National Institute of Mental Health (NIMH), which partly funded the work. “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.”