From The Quarterly, Summer 2013

With the support of a NARSAD Independent Investigator Grant, Debby W. Tsuang, M.D., and her colleagues at the University of Washington* have applied an innovative approach to uncover elusive, genetic variants associated with schizophrenia susceptibility. Their findings, published online on April 3rd in JAMA Psychiatry, provide a new tool in the search to understand how aberrant genes undermine molecular pathways in the brain to cause schizophrenia and related mental illnesses and suggest possible new targets for treatment.

Schizophrenia is an extremely complex, highly heritable genetic disorder. The more commonly used genetic methods through which causative genes have been identified in many disorders have been less successful for finding candidate genes for schizophrenia and the identification of specific causative genes has been elusive. The genetic variants so far identified as being associated with schizophrenia, Dr. Tsuang points out, “only account for slightly increased risks. It is likely that the majority of patients carry multiple genetic variants, along with environmental risk factors to develop the disorder.”

On the other hand, there may be unique families who carry rare novel genetic variants that have eluded discovery until recently. One novel method for gene identification is genomic sequencing, to detect any genetic variants in the entire DNA sequences the genome of an organism. DNA is composed of smaller units called nucleotides. When looking for very rare variants, Dr. Tsuang explains, “sequencing every one of the three billion nucleotides in the human genome is still expensive. However, it is feasible, to sequence the exome, the areas that contain the coding regions or exons, of all genes.” Exons make up less than 5% of the genome but are believed to harbor disease-causing mutations.

Dr. Tsuang is Professor of Psychiatry and Behavioral Science at the University of Washington School of Medicine and is also the Director of the Geriatric Research Education and Clinical Center at the VA Puget Sound Health Care System. For her NARSAD Grant-funded project, she selected five large families enrolled in the National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders Initiative. Each family had multiple affected members: among the 41 subjects, 18 had schizophrenia, four had schizoaffective disorder or depression and two had unspecified psychosis. Seventeen were unaffected.

In all five families, exome sequencing detected rare variants unique to each family in one of three genes that are in the N -methyl-D-aspartate (NMDA) receptor pathways. The NMDA receptor is involved in transmitting glutamatergic signals. Glutamate is one of the brain’s most important inhibitory neurotransmitters. These genes, mGluR5, PPEF2, and LRP1B, may represent novel targets for medications to treat schizophrenia.”

Dr. Tsuang says, “Our findings suggest that exome sequencing in multiplex pedigrees can be an effective strategy to gene discovery in complex disorders like schizophrenia. Because of the generous funding of the NARSAD Grant, we were able to uncover new genes associated with the risk of developing schizophrenia.



The Takeaway:

Applying a novel technique to study families in which many members have mental illness is uncovering previously unidentified risk genes, primarily for schizophrenia.

 

Debby W. Tsuang, M.D.

Professor of Psychiatry and Behavioral Science, University of Washington School of Medicine; Director of the Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System;

2001 NARSAD Young Investigator Grantee

2009 NARSAD Independent Investigator Grantee

*In addition to Dr. Tsuang the first author on this publication is Andrew Timms, post-doctoral fellow in Dr. Marshall Horwitz’ laboratory and second author is Michael O. Dorschner of the UW Department of Psychiatry and Behavioral Sciences and the Puget Sound Veterans Administration Health Care System.  Other scientists on the study were Jeremy Wechsler and Robert Kirkwood, of the UW Department of Pathology;  Carl Baker and Evan Eichler of the UW Department of Genome Sciences; and Olena Korvatska of the UW Department of Medicine, Division of Medical Genetics; Kyu Yeong Choi and Katherine W. Roche, of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health;  Santhosh Girirajan of the Departments of Biochemistry and Molecular Biology and Anthropology at Pennsylvania State University.