Studies ID Molecular Accomplices of Suspect Schizophrenia Genes
NIMH-funded researchers have discovered how certain genes work at the molecular level to increase the risk of schizophrenia. Their findings are among the first to suggest a biological basis for two of the most compelling schizophrenia risk genes. Study authors Barbara Lipska, Ph.D., Amanda J. Law, Ph.D., Daniel R. Weinberger, M.D., Joel E. Kleinman, M.D. and colleagues at NIMH revealed these findings in two papers published in the March 1, 2006 advanced online issue of Human Molecular Genetics (Lipska et al.) and the April 25 issue of the Proceedings of the National Academies of Science (Law et al.).
Previous genetic studies have identified two genes as schizophrenia risk genes—Disrupted-in-Schizophrenia 1 (DISC1) and neuregulin 1—but the way in which they work has been unclear. DISC1 is important for brain development, particularly, the development of the limbic system, the brain's memory and emotion hub. Neuregulin 1 controls the construction and wiring of the brain during development, communication between nerve cells, and adaptations to new situations.
Lipska and colleagues examined post-mortem tissue from human hippocampi and prefrontal cortices, brain regions strongly implicated in schizophrenia, to determine how DISC1 is expressed during human brain development and whether DISC1 and several molecules it interacts with are abnormally expressed in schizophrenia. They also tested whether certain high-risk variants of DISC1 were more likely to be abnormally expressed. They found that DISC1 expression peaks in infancy, suggesting that DISC1 plays an important role in human brain development. Although altered expression of DISC1 was not found to significantly contribute to schizophrenia risk, the expression of three molecules (NUDEL, FEZ1 and LIS1) that work in concert with DISC1 was reduced in people with the illness. This reduction was associated with high risk variants of the DISC1 gene. Failure of DISC1 to bind to these partners may lead to their altered expression and to disruptions in brain and nervous system development, initiating a cascade of events that leads to psychotic disorder, the study suggests.
Law and colleagues hypothesized that alterations in the expression of certain types of neuregulin 1 in the brain may explain the genetic association with schizophrenia. They compared post-mortem tissue from the hippocampi of patients with schizophrenia and those without the disease, looking at four types of the neuregulin 1 gene. They tested whether the expression of these four gene products was abnormal in the brain in schizophrenia and whether genetic variants within the neuregulin 1 gene, previously associated with the disease, were linked to their abnormal expression. The NIMH researchers found that the expression of one product of neuregulin 1 (called type I) was increased in patients with schizophrenia and that altered expression of this gene product may contribute to increased risk of schizophrenia. Furthermore, expression of a novel type of neuregulin 1 in the brain that was first discovered in Iceland (called type IV) was also increased and found to significantly contribute to increased risk of schizophrenia. The study suggests that these genetic variants of neuregulin 1 potentially interfere with proteins involved in the gene's regulation. The researchers propose that in patients with schizophrenia, altered regulation of neuregulin 1 expression likely disrupts the gene's signaling, which affects brain development and plasticity, thus contributing to the development of the disease.
Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, Mitkus S, Weickert CS, Matsumoto M, Sawa A, Straub RE, Vakkalanka R, Herman MM, Weinberger DR, Kleinman JE. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum Mol Genet. 2006 Apr 15;15(8):1245-58.
Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, Harrison PJ, Kleinman JE, Weinberger DR. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc Natl Acad Sci USA. 2006 Apr 25;103(17):6747-52.