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Schizophrenia’s Strongest Genetic Link
Mar 29, 2018

Grace Armstrong
Core Spirit member since Dec 24, 2020
Reading time 2 min.

The discovery of a runaway gene is being touted as one of schizophrenia’s greatest breakthroughs. Researchers have discovered a gene that prunes away communication infrastructure in the brain, and when this gene prunes too much, schizophrenia can develop. This finding offers hope for detection, treatment, and possibly prevention of this largely mysterious but devastating disease.

A team of NIH-funded scientists in Massachusetts examined the genomes of 65,000 people (about 29,000 of whom had schizophrenia), 700 postmortem brains, and genetically engineered mice to examine genetic risks related to schizophrenia. The gene they discovered, called complement component 4, or C4, is one of more than 100 chromosomal sites that are already known to be associated with schizophrenia. Most of the already-identified genes are related to neurodevelopment, neuroplasticity, immunology, and neuroendocrinology.

C4 has known roles in immunity, but it was interesting to schizophrenia researchers because it is highly variable among individuals: people have different numbers of copies of the C4 gene and distinct DNA sequences that can make the gene work differently in different people. Note that this is not normally how most genes work, which made the C4 gene a puzzling subject to investigate.

The C4 protein produced by the gene supports connections between neurons in the brain (synapses). When the brain is maturing, the C4 protein prunes synapses that are no longer needed, thus optimizing the brain’s performance. In humans, most of this pruning and streamlining of the brain’s synapses occurs during the late teenage years or early adulthood. Not so coincidentally, this is the same time as the onset of most cases of schizophrenia.

The gene is expressed primarily in two main forms: C4A and C4B. The more C4A that is present in the brain, the greater the risk for schizophrenia. Essentially, the more C4, the more pruning, and the more lost synapses.

Schizophrenia is characterized by hallucinations, delusions, dysfunctional thought processes, and agitated body movements. Current treatments, including antipsychotic medications, only treat the symptoms of the disease and not the underlying cause. To date, genetic and environmental factors have been suspected of increasing the risk of schizophrenia, including psychosocial stress, cannabis use, and living in urban areas.

Schizophrenia affects about 1% of the US population and 21 million people worldwide. It is believed to be almost entirely heritable, but the specific genetic activities related to its development and the precise pathogenesis of this complex disease have been largely unknown until now. The discovery of the relationship between C4 and brain maturation changes the focus of schizophrenia research, potentially leading to early detection, novel treatments to counteract excessive C4 activity, and even prevention in those at risk of the disease.

by Jennifer Gibson For Brain Blogger


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