Excessive synaptic pruning in the maturing brains of adolescents may help to explain the biological cause of schizophrenia.
According to a landmark study published in Nature, the study builds on population-level research that has shown that the strongest genetic associations for schizophrenia are variations in the major histocompatibility complex (MHC) locus.
The MHC locus has 3.6 million bases, with variants linked to schizophrenia found throughout it, and “is one of the most challenging problems in human statistical genetics,” wrote Ryan S. Dhinsa, MD, PhD, and David B. Goldstein, PhD, in an accompanying editorial.
The new study uses genome-wide association (GWAS) to identify alleles of the complement component 4 (C4) gene within the MHC locus. Humans have variations of either C4-A or C4-B—the number of copies of the gene varies as does the presence of a long or short version of the gene.
“To date, few GWAS associations have been explained by specific functional alleles. An unexpected finding at C4 involves the large number of common, functionally distinct forms of the same locus that appear to contribute to schizophrenia risk,” wrote authors from the study.
After analyzing the genomes of more than 64,000 participants, the researchers identified the C4-A gene as a key factor in schizophrenia risk. People with schizophrenia were more likely to have an overactive form of C4-A that is linked with excessive synaptic pruning.
When functioning properly, synaptic pruning in early adulthood eliminates unneeded connections and helps the brain to perform more efficiently, but too much pruning can lead to impairment. Previous studies have shown cortical thinning and reduced synaptic structures in the brains of individuals with schizophrenia, and this new finding supports the role of pruning in schizophrenia, as well as provides compelling evidence of a biological cause. The timing of synaptic pruning also coincides with the early adulthood onset of schizophrenia, lending strength to the hypothesis.
Although the new study does not have an immediate clinical implication, researchers hope it will allow them to design therapies that target the mechanism underlying the disease.
