McLean Hospital Researchers Find Inherited Pathway of Risk for Schizophrenia

February 25, 2014

Schizophrenia is one of the most disabling of all psychiatric illnesses. Sadly, it is not uncommon and it strikes early in life. Many studies have looked into causes and potential interventions, and it has been long known that genetic factors play a role in determining the risk of developing schizophrenia. However, recent work has shown that there will be no simple answers as to why some people get schizophrenia: No single gene or small number of genes explains much of the risk for illness. Instead, future studies must focus on larger numbers of interacting genes. In a new paper published in PLOS ONE (doi: 10.1371/journal.pone.0089441), McLean Hospital researchers Bruce M. Cohen, MD, PhD, Dost Öngür, MD, PhD; Massachusetts General Hospital researchers Laramie Duncan, PhD, Jordan Smoller, MD, ScD, and Phil Hyoun Lee, MS, PhD; Colm O’Dushlaine, PhD, of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard; and Peter Holmans, MSc, PhD, of the Cardiff University School of Medicine in Wales, report promising evidence on what one of those important groups of genes may be.

Previous studies of schizophrenia have shown abnormalities in the brain’s white matter—wiring and insulation—but these studies could not definitively separate inherited from environmental causes. Previously discovered anomalies were used in this study to select likely assortments of genes that, as a group, might be highly determinative of the risk for schizophrenia. The choice of genes was based on convergent results of past studies conducted locally and around the world, and included genes that control the insulation of the nerve cells in the brain. The results of this study are important because they strongly suggest that the abnormalities of wiring and insulation are substantially determined by genes.

“There is abundant evidence from our center and from other laboratories that this insulation is compromised in schizophrenia,” said study co-author Cohen, director of the Shervert Frazier Research Institute at McLean Hospital. “Based on this lead, we tested whether the genes required for the activities of the cells that make this insulation (oligodendrocytes) were associated with schizophrenia. In a primary analysis, followed by three separate means of confirmatory analysis, we found strong evidence that genes for oligodendrocytes, as a group, were indeed associated with schizophrenia.”

The findings of this study suggest a concrete reason why insulation is disrupted in the brain in schizophrenia. This disruption, in turn may explain why thinking is altered in schizophrenia because nerve cells are unable to pass exact messages if they lack proper insulation. Further, the findings show that the abnormality in insulation is genetically determined. It is not due to years of treatment or to different life activities or exposure to toxins in the environment. Finally, the results identify a specific cell level abnormality, in oligodendrocytes, in schizophrenia. Similar findings, using different techniques, were recently reported by an independent group of investigators, working separately but contemporaneously with the authors of this study.

“Knowing that one of the pathways of risk for schizophrenia is in this set of genes and in these cells may help identify who is at risk and in what way they are at risk,” said Cohen. “The cells themselves will next be studied to define the problem and seek methods to prevent or reverse it. Thus, the findings can point us towards new ways to reduce the risk and burden of schizophrenia.”

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