Comprehensive Identification of Key Genetic Players in Schizophrenia

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Alexander Niculescu, III, M.D., Ph.D., NARSAd Young Investigator Grantee, Expert on Schizophrenia
Alexander Niculescu, III, M.D., Ph.D.

From The Quarterly, Summer 2012

Alexander Niculescu, III, M.D., Ph.D., and an international team of scientists have identified and prioritized the top genes—from among thousands of potential candidates—that play key roles in the pathology of schizophrenia. This opens the possibility for greater accuracy in the prediction of schizophrenia risk, improved and perhaps earlier diagnoses and the development of more effectively targeted therapeutic interventions.

Announced online on May 15 in the journal Molecular Psychiatry, the authors note that the analysis “is arguably the most comprehensive integration of genetics and functional genomics to date in the field of schizophrenia, yielding a comprehensive view of genes, blood biomarkers, pathways and mechanisms that may underlie the disorder.”

To achieve this, Dr. Niculescu and colleagues used an approach that they pioneered over the years called convergent functional genomics (CFG), which combines data from many different types of studies, including genome-wide association studies, genetic linkage studies and gene expression data from human tissue samples and animal models.

The researchers began their search by casting ‘a wide net,’ generating an initial list of 3,194 different genes that in previous studies had shown some evidence of association with schizophrenia. Evidence leaned heavily on the presence of particular variations in DNA sequences in the genes of schizophrenia patients. Such variations are called single nucleotide polymorphisms, or SNPs (pronounced ‘snips’). Using an ascending scoring scale based on CFG, the team pinpointed 186 genes with a score of 3 or above; 42 with a score of 4 or above; and, at the top of the list, four genes with a score of 5, among them the Disrupted-in-Schizophrenia 1 (DISC1) gene, known to influence neuronal development and neuronal connectivity.

"At its core, schizophrenia is a disease of decreased cellular connectivity in the brain, precipitated by environmental stress during brain development among individuals with genetic vulnerability,” explains Dr. Niculescu, Associate Professor of Psychiatry and Medical Neuroscience at the Indiana University School of Medicine and Director of the Laboratory of Neurophenomics at the university’s Institute of Psychiatric Research, the principal investigator for the study.

Dr. Niculescu’s team, along with colleagues from the Washington, D.C. VA Medical Center; Trinity College, Dublin; the University of California, San Diego; Scripps Research Institute; and Cardiff University, UK; went on to show how these top genes can be used to generate a genetic risk prediction score to aid in the diagnosis of schizophrenia, based on the presence or absence of SNPs associated with the illness. Finally, they compared the top candidate genes for schizophrenia with top candidate genes for bipolar disorder and anxiety disorders and found a significant genetic overlap.
 
Dr. Niculescu expressed the hope that “by better understanding the genetic and biological basis of the illness, we can develop better tests as well as better treatments.”

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