Neurology Central

Novel insight into the genetic basis of schizophrenia revealed

Genetic analysis of almost 65,000 individuals with and without schizophrenia has revealed that schizophrenia risk is increased as a result of the inheritance of gene variants linked to synaptic pruning. The study, which was published recently in Nature, represents the first described association between specific gene variants and the biological processes underlying the psychiatric disorder.

Despite originally being described over 130 years ago, to date there is still a lack of effective treatments for patients suffering from schizophrenia. In 2014 an international consortium led by a team at the Broad Institute (MA, USA) successfully identified over 100 human genome regions carrying risk factors for schizophrenia. The new study, also from the Broad Institute, builds on these findings, presenting the specific gene associated with strongest of these risk factors, synaptic pruning.

The influential gene was identified as complement component 4 (C4), a gene previously known to play a role in the immune system but not previously in brain development or schizophrenia. C4 was shown to exhibit a high degree of structural variability between individuals. When gene structure was compared to gene activity, measured in almost 700 post-mortem brain tissues, it was discovered that gene structure was a predictor of gene activity. Specifically, individuals with particular structural forms of C4 exhibited increased gene expression and consequently an increased risk of schizophrenia development.

Further analysis of the role of C4 in the brains of mice revealed additional information about the mechanism underlying the link between certain C4 structural forms and increased schizophrenia risk. C4 was shown to be key in controlling the pruning of synapses during the maturation of the brain. Specifically, C4 was essential for the deposition of the protein termed C3 onto synapses – a signal for the synapses to be pruned. The more C4 activity in the animal, the greater synapse loss was exhibited during the maturation period.

The findings help to explain some well-know features of the disorder, including its typical onset period in adolescence, and the reduction in synapses and thinner cerebral cortex seen within the brains of schizophrenic patients. In addition, the results point to a potential new target for drug development to prevent the pruning of synapses in individuals with early signs of schizophrenia.

“For the first time, the origin of schizophrenia is no longer a complete black box,” commented Eric Lander (Broad Institute).

“This study marks a crucial turning point in the fight against mental illness,” remarked Bruce Cuthbert (National Institute of Mental Health). “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

Beth Stevens (Broad Institute) concluded: “We’re far from having a treatment based on this, but it’s exciting to think that one day, we might be able to turn down the pruning process in some individuals and decrease their risk.”

Sources: Broad Institute press release