Two independent studies conducted by scientists in the United Kingdom and the United States show that rare genetic changes found in the DNA of people with schizophrenia are clustered in proteins that manage the strength of connections and the communication between brain cells. Published January 22nd in the journal Nature, the two studies together make up the largest genetic study of its kind, where scientists analyzed the protein-encoding parts of the genome (the “exome”) to identify what are called point mutations in the DNA.
The researchers, including several current and former NARSAD Grantees, found rare point mutations in many different genes, reinforcing the long-held belief that there is no one schizophrenia gene. They also discovered, however, that while the point mutations hit many different genes, these genes encode proteins that work together at the synapse to facilitate communication between neurons. It has long been suspected that schizophrenia might stem from problems at the synapse, but there has been no conclusive evidence.
“We found out that the rarest, most severe point mutations—the most likely to damage a protein—contribute to schizophrenia risk,” said former NARSAD Grantee Dr. Pamela Sklar of the Icahn School of Medicine at Mount Sinai, who was an author on both studies. Dr. Sklar co-led one study with Dr. Shaun Purcell of The Broad Institute of Harvard and the Massachusetts Institute of Technology. They analyzed the DNA of 2,536 people with schizophrenia and 2,543 control subjects.
“Despite the considerable sample sizes, no individual gene could be unambiguously implicated in either study. Taken as a group, however, genes involved in neural function and development showed greater rates of disruptive mutations in patients,” said Dr. Purcell, a 2006 NARSAD Young Investigator Grantee. “That finding is sobering but also revealing. It suggests that many genes underlie risk for schizophrenia and so any two patients are unlikely to share the same profile of risk genes.”
The second study, led by 2012 Brain & Behavior Research Foundation Lieber Prizewinners Drs. Michael O’Donovan and Michael Owen of Cardiff University in the United Kingdom, analyzed DNA of 623 people with schizophrenia and their parents to look for new or “de novo” mutations. De novo mutations are carried by the person with schizophrenia but not by either parent and they are thought to have the potential to be more damaging.
Dr. Owen, Director of the Institute of Psychological Medicine and Clinical Neurosciences, said that “this degree of convergence from several studies is unprecedented in schizophrenia genetics and tells us that for the first time we have a handle on one of the core brain processes that is disrupted in the disorder.”
“The major insight of this research is that we’ve identified an area of biological function that is relevant to schizophrenia, and the causes of schizophrenia. We’ve not been able to say that with any confidence before,” added Dr. O'Donovan, Deputy Director of the Institute of Psychological Medicine and Clinical Neurosciences. The findings also point to an overlap with the causes of other brain disorders such as autism and intellectual disability, the researchers report. "The fact we’ve been able to identify a degree of overlap between the underlying causes of schizophrenia and those in autism and intellectual disability suggests that these disorders might share some common mechanisms,” reported Dr. O’Donovan.
Other NARSAD Grantees that were involved in this research include: 2013 NARSAD Young Investigator Grantees Panagiotis Roussos, M.D., Ph.D., and Eli Stahl, Ph.D., of the Icahn School of Medicine at Mount Sinai; 2012 NARSAD Young Investigator Grantee Sarah Bergen, Ph.D., of the Karolinska Institutet in Stockholm, Sweden (formerly of the Broad Institute of the Massachusetts Institute of Technology); 2010 NARSAD Distinguished Investigator Grantee Patrick Sullivan, M.D., of the University of North Carolina School of Medicine; and 2007 NARSAD Young Investigator Grantee Stephen Haggarty, Ph.D., of the Broad Institute.
Read the abstracts of both of these research studies from Nature:
- A polygenic burden of rare disruptive mutations in schizophrenia
- De novo mutations in schizophrenia implicate synaptic networks
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