Working in conjunction with researchers at the Harvard Medical School Partners Center for Genetics and Genomics in Boston, MA, the Zucker Hillside team utilized a cutting-edge technology called whole genome association (WGA) to search the entire human genome in 178 patients with schizophrenia and 144 healthy individuals. WGA technology was used to examine over 500,000 genetic markers in each individual, the largest number of such markers examined to date, and the first published study to utilize WGA technology in a psychiatric illness. Previous studies have been much more limited in scope, often incorporating less than 10 markers.
The study results are scheduled to be published online Tuesday in Molecular Psychiatry, which can be accessed at http://www.nature.com/mp/journal/vaop/ncurrent/index.html.
Of the 500,000 genetic markers, the researchers found that the most significant link with schizophrenia came from a marker located in a chromosomal region called the pseudoautosomal region 1 (PAR1), which is on both the X and Y chromosomes. The marker was located adjacent to two genes, CSF2RA and IL3RA, which previously were thought to play a role in inflammation and autoimmune disorders. Those two genes produce receptors for two cytokines, GM-CSF and interleukin-3. Cytokines are involved in the body’s response to infection, and may play a role in the brain’s response to injury.
By then examining the DNA sequence of those genes in a separate group of patients with schizophrenia and healthy individuals, the research team – working in conjunction with PGx Health in New Haven, CT -- observed multiple gene abnormalities in patients with schizophrenia that were not found, or were found much less commonly, in healthy individuals.
“WGA technology allowed us to shine a light across virtually the entire genome, rather than looking at just one gene at a time,” said Todd Lencz, PhD, the first author of the study, and an investigator at Zucker Hillside and The Feinstein Institute. “Using WGA, we found genes that had not been previously considered in studies of schizophrenia.” Dr. Lencz added that “the critical next step is confirming these results in independent datasets.”
Anil Malhotra, MD, also of Zucker Hillside and The Feinstein, and senior investigator of the study, noted: “If these results are confirmed, they could open up new avenues for research in schizophrenia and severe mental illness. A role for cytokines could help explain why prenatal exposure to viruses is a risk factor for schizophrenia, thus providing a bridge between genetic risk and environmental exposures.”
The study was funded by a private donation from the Donald and Barbara Zucker Foundation, an award from the KeySpan Energy, and grants from the National Institute of Mental Health; NARSAD, the Mental Health Research Association (formerly known as National Alliance for Research on Schizophrenia and Depression); and the Stanley Medical Research Institute.
About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, and part of the North Shore-LIJ Health System, The Feinstein Institute for Medical Research is among the top six percent of all institutions that receive funding from the National Institutes of Health. Building on its strengths in neurodegenerative and psychiatric disorders, genomics and human genetics, immunology and inflammation, and oncology and cell biology, its goal is to understand the biological processes that underlie various diseases and translate this knowledge into new tools for diagnosis and treatment.
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