Massive genomic study provides intriguing insights into Schizophrenia




Schizophrenia is one of the most debilitating mental illness that changes the way a person thinks, acts, expresses emotions, perceives reality, and relates to others. The disorder, which is not age or gender- specific, has always been treated only for its symptoms since the genetic cause was an enigma, up until now. Scientists from the Broad Institute, Harvard Medical School and Children’s Hospital in Boston, led by Steven McCaroll, have found a specific gene responsible for ‘eating up’ synapses and leading to an abnormal loss of grey matter.

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There is a natural pruning process that the human brain employs to remove brain cell connections that are not required, to improve efficiency of other neuronal transmissions. This brain plasticity explains the way our learning and memory works and how we remember stuff that we revise or recollect more often. When this process goes on an overdrive, it is known to cause a range of mental illness including schizophrenia.


The culprit gene identified from a massive genetic study

The ever quickening advances of science made possible by the success of the Human Genome Project will also soon let us see the essences of mental disease. Only after we understand them at the genetic level can we rationally seek out appropriate therapies for such illnesses as schizophrenia and bipolar disease – James D. Watson 

And this landmark finding has the potential to fulfill the nobel laureate’s prophecy. The researchers analysed more than 64,000 human genomes (including healthy and schizophrenic patients) from 22 different countries to locate regions of the human genome harboring genetic variants that increase the risk of schizophrenia. The strongest signal was on chromosome 6, which homed around hundreds of genes and initially confounded the team.

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The first author, Aswin Sekar, an MD-PhD student at HMS, identified a pattern, which pointed to a gene called C4, whose protein levels correlated with the risk of developing schizophrenia. The C4 protein is well known for its role in the immune system, and via a process called ‘complement cascade’ rapidly recognizes and eliminates pathogens and cellular debris.

The combined effort of analysing the massive genetic data by experts in the field of molecular biology, developmental neurobiology and immunology, has yielded an unexpected candidate gene C4. The team found that mice lacking C4, had reduced synaptic pruning compared to their wild type littermates, thus providing direct evidence of C4 in synaptic refinement.

For a disease in which only the symptoms have been treated so far, understanding the basic genetic mechanism, has the potential to treat the main disease and also address the more serious problems of cognitive loss and emotional withdrawal. The study is extremely promising and identification of a specific gene, has the following main implications:

  • Will lead to developing animal models to understand the disease mechanism
  • Design therapeutic drugs to target the upregulated C4 protein and find a balance so as not to affect the normal immune functioning.
  • Testing can be done to identify those at risk, and help prevent the onset of psychosis.

Does the C4 protein involve all the downstream proteins in its complement cascade in synaptic pruning? If so, will therapeutic targeting of C4 compromise the innate immunity? It remains to be seen if this trend in genetic variation of C4 exists across Asians and other ethnic groups of the world. These are some of the questions that could be addressed in the future studies.

The original paper can be accessed here