Rare mutations in specific sets of genes may increase one’s chances of developing schizophrenia, according to investigators at Icahn School of Medicine at Mount Sinai, who recently led one of the largest and most comprehensive exome-sequencing studies of the psychiatric illness.
The findings, documented in two studies in the January 22, 2014, online issue of Nature, are helping researchers piece together the complex genetic architecture involved in schizophrenia, a chronic, debilitating illness that affects approximately 1 percent of the world’s population, including 2.4 million Americans. The studies showed that some of the same genes implicated in schizophrenia also are associated with autism and intellectual disability.
“Many different DNA changes, some rare and some common in the population, affect a person’s risk of developing schizophrenia,” says Pamela Sklar, MD, PhD, Chief of the Division of Psychiatric Genomics, and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai, who was one of the lead investigators. “We are working through all of the kinds of changes and examining them, so that we can understand the genetic risk factors that lead to schizophrenia.”
Dr. Sklar and Shaun Purcell, PhD, the studies’ co-lead investigator, who is Associate Professor of Psychiatry at Icahn School of Medicine, collaborated with researchers from major institutions around the world, including Sweden, the United Kingdom, Bulgaria, and the United States.
One of the studies sequenced all of the genes of 2,536 patients with schizophrenia and 2,543 controls, with DNA samples collected by researchers at the Karolinska Institute in Sweden. The other study performed exome sequencing on 623 “trios” from Bulgaria, comprised of patients with schizophrenia and their parents.
“This is the most comprehensive look at the rare coding variants involved in schizophrenia to date,” says Dr. Purcell. “The sheer volume of data generated in these projects is remarkable and the findings suggest new ways of thinking about the role of rare mutations in schizophrenia, given the large number of genes implicated and the synaptic biology to which they point.”
Over the years, limited accessibility to the brain has made the organ uniquely difficult to study. With little direct information about brain tissue, and no available blood tests, schizophrenia and other mental illnesses are diagnosed solely by examining the patient’s behavior.
The studies represent the first of many more steps that will be needed to truly understand the illness. Down the line, says Dr. Sklar, the researchers will examine what drives the mutations and why some lead to autism instead of schizophrenia. They will also use stem-cell technology to manipulate cells, and to see whether early interventions can improve a patient’s prognosis.
“Despite the fact that we have known for decades that schizophrenia is highly heritable—with 65 percent to 80 percent of the risk being genetic—it has not been possible to identify individual genes that comprise that risk,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of The Friedman Brain Institute at Mount Sinai. “These exciting new discoveries provide a path not only for a better understanding of the biological basis of schizophrenia, but also for developing fundamentally more effective ways of treating and, ultimately, preventing the illness.”