Study Explores Gene Linked to Schizophrenia

Two scientists do research in a labA variant in a gene that escalates synaptic pruning—a process that removes neurons from the brain that are no longer useful—could be linked to schizophrenia, according to a large study published in Nature.

Schizophrenia affects about 1% of the adult population and produces a range of symptoms, including delusions and auditory hallucinations.

The Link Between C4 and Schizophrenia

Researchers from the Broad Institute and Harvard University studied the genomes of 64,785 people to explore genetic links to schizophrenia. They found a clear connection between symptoms of schizophrenia and possession of a mutation in the complement component 4 (C4) gene, which has previously been known to help a person’s immune system to identify and target infections.

C4 is one of at least 100 genes that have been linked to schizophrenia, meaning it is not the sole cause of the condition. However, it may be the most significant. When researchers plotted the gene alongside other schizophrenia-related genes, mutant forms of C4 towered above all other genes associated with the condition.

Synaptic Pruning and Schizophrenia

Synaptic pruning is key to understanding the connection between C4 and schizophrenia. Schizophrenia typically appears during adolescence, which is also a time of rapid growth in the brain. Brain growth is usually followed by synaptic pruning, removing unnecessary or redundant connections.

The process itself does not cause schizophrenia, but research has already shown people with schizophrenia have fewer brain connections and less gray matter. According to the study, the mutant form of C4 may tell the immune system to destroy too many synaptic connections in the brain, increasing the risk of schizophrenia.

Could This Change Schizophrenia Treatment?

Jeffrey Lieberman, MD, a renowned schizophrenia researcher, was the president of the American Psychiatric Association (APA) from May 2013 to May 2014. He explained the potential implications of the study.

“The schizophrenia phenotype has long been associated with loss of gray matter in the brain,” Lieberman said. “Now that we have more information about what underpins this phenomenon, we are closer to understanding schizophrenia.”

The research will not change schizophrenia treatment today, Lieberman explained, but could open new avenues for future treatment. Slowing down the pruning process in people who are genetically vulnerable to schizophrenia might one day be possible, potentially reducing the incidence or severity of the condition.

Tips for People with Schizophrenia

Lieberman’s 2015 book, Shrinks: The Untold Story of Psychiatry, tells the tale of the discipline’s transformation from a speculative endeavor to an experimental, evidence-based science. The book highlights many of psychiatry’s missteps: lobotomies, hydrotherapy, and primal scream therapy, to name a few.

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As a psychiatrist and long-time advocate for mental health issues, Lieberman believes people with schizophrenia often do not get high-quality care.

“People with schizophrenia and other severe mental illnesses have long suffered from a kind of benign neglect,” he said. “Doctors often settle.”

Good schizophrenia treatment is typically a mix of several strategies, Lieberman said, including medication, supportive psychotherapy, psychoeducation, supportive educational and employment settings, and effective case management. Because schizophrenia has no cure, people with schizophrenia sometimes encounter economic, institutional, and other barriers to treatment.

“The patient should be the barometer for what is working,” Lieberman said.

He suggests the following strategies for people with schizophrenia who want highly effective treatment:

  • Push your doctor. Each medication used should have a clear and rational justification. According to Lieberman, doctors sometimes continue prescribing a medication even when its benefits are unclear or minimal. Instead, providers should partner with the people they are treating to assess the value of each drug while working to limit side effects.
  • Read reliable online information. Lieberman cautions that online information may not be credible and suggests people rely on sites such as the National Institutes of Health, hospital sites, and universities—not message boards or anonymous blogs. Information on these sites can better equip mental health consumers to ask intelligent questions and pursue effective treatments.
  • Seek a second opinion. “No good doctor should be threatened by a second opinion. If you are not sure where to seek a second opinion, contact your local medical school’s department of psychology and ask for a referral,” Lieberman said.


  1. Courage, K. H. (2016, February 1). Variations in a gene provide clues about schizophrenia. Retrieved from
  2. Sekar, A., Bialas, A. R., Rivera, H. D., Davis, A., Hammond, T. R., Kamitaki, N. . . . Mccarroll, S. A. (2016). Schizophrenia risk from complex variation of complement component 4. Nature, 000. doi:10.1038/nature16549
  3. Schizophrenia’s strongest known genetic risk deconstructed | National Institutes of Health (NIH). (2016, January 27). Retrieved from

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  • Beck


    February 8th, 2016 at 10:11 AM

    you have to hope that there becomes a way to diagnose this earlier

  • Beatrice


    February 8th, 2016 at 3:04 PM

    I know that for some readers this probably seems like small steps indeed, but we have to look at it as it is at least a small step in the right direction. Anything that can take us closer to the information that we are seeking is always a good thing. Give it time, and one day, hopefully soon, all of the answers will be there.

  • layne


    February 10th, 2016 at 11:26 AM

    Can anyone explain to me why this would be a genetic trait that is always present but does not seem to manifest until later adolescence?

  • Zawn Villines

    Zawn Villines

    February 10th, 2016 at 11:49 AM

    Layne, that’s a really great question. The simple answer is that this is a gene for a process that does not occur until adolescence: synaptic pruning. Once the pruning begins, the gene causes it to escalate out of control, potentially leading to schizophrenia, in at least some people who have the gene.

    Think of it this way: if you have a gene for a pregnancy-related condition, that gene will only affect you if you get pregnant. This is the same sort of thing.

  • layne


    February 11th, 2016 at 3:37 PM

    Thanks Zawn! That was very helpful. So let’s go a bit further with this… is there anything like genetic modification or even something that could suppress the behavior of that gene at a certain point so that schizophrenia would not present? Or is that just getting into medical ethics that have not been explored or tackled yet?

  • Tanner


    February 12th, 2016 at 1:10 PM

    weird how something that also affects immune system and infection could be related to this

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