The Biochemical Pharmacology Discussion Group and the Biochemical Group of the New York Section of the American Chemical Society
Searching for Schizophrenia: DISC1 and the Developmental Hypothesis
Posted July 21, 2008
Schizophrenia is a psychiatric disorder affecting about 1% of the population worldwide. It appears to be as much as 80% under genetic control, but the search to find one single gene that accounts for the diverse symptoms of the disorder has been frustrating. More recently, this quest has been abandoned, replaced by the hypothesis that schizophrenia is a polygenic disorder, likely of developmental origin.
By this hypothesis, an underlying genetic propensity—in all likelihood combined with an early environmental influence—disrupts typical neurodevelopment, causing the symptoms of schizophrenia to arise late in cortical maturation. The gene DISC1, which plays an important role in neuronal migration and integration and has been associated with schizophrenia, is one of the many contenders for this role. This theory of pathogenicity and the mechanisms that could underlie it were the focus of a May 27, 2008, meeting at the Academy.
This Web site has a wealth of information on research into the disease. Important new papers are posted weekly, along with commentary by researchers in the same field. Among other resources, the site has archived a virtual roundtable discussing advances in DISC1 research, led by David Porteous.
National Alliance on Mental Illness
For patients, the National Alliance on Mental Illness has a fact sheet on schizophrenia and related disorders, as well as links to resources and information about medications.
Sawa, A., McInnis, MG. 2007. Neurogenetics of Psychiatric Disorders (Medical Psychiatry). Informa Healthcare, New York.
O'Donnell, P. 2007. Cortical Deficits in Schizophrenia: From Genes to Function. Springer, New York.
Reviews on DISC1
Chubb JE, Bradshaw NJ, Soares DC, et al. 2008. The DISC locus in psychiatric illness. Mol Psychiatry 13:36-64.
Millar JK, Mackie S, Clapcote SJ, et al. 2007. Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness. J. Physiol. 584: 401-405.
Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ.2008. How has DISC1 enabled drug discovery? Mol. Cell Neurosci. 37: 187-195.
St Clair D, Blackwood D, Muir W, et al. 1990. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336: 13-16.
Hennah W, Tomppo L, Hiekkalinna T, et al. 2007. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum. Mol. Genet. 16: 453-462. Full Text
Ishizuka K, Paek M, Kamiya A, Sawa A. 2006. <ahref="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16797264" target="_blank">A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol. Psychiatry 59: 1189-1197.
Millar JK, Wilson-Annan JC, Anderson S, et al. 2000. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9: 1415-1423. Full Text
Kamiya A, Kubo K, Tomoda T, et al. 2005. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat. Cell Biol. 7: 1167-1178.
Hikida T, Jaaro-Peled H, Seshadri S, et al. 2007. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc. Natl. Acad. Sci. USA 104: 14501-14506. Full Text
Kamiya A, Tomoda T, Chang J, et al. 2006. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum. Mol. Genet. 15: 3313-3323. Full Text
Camargo LM, Collura V, Rain JC, et al. 2007. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol. Psychiatry 12: 74-86.
Camargo LM, Wang Q, Brandon NJ. 2008. What can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology? Novartis Found. Symp. 289: 208-216; discussion 216-21, 238-40.
Hayashi MA, Portaro FC, Bastos MF, et al. 2005. Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1. Proc. Natl. Acad. Sci. USA 102: 3828-3833. Full Text
Katherine E. Burdick
Burdick KE, Kamiya A, Hodgkinson CA, et al. 2008. Elucidating the relationship between DISC1, NDEL1, and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. Hum. Mol. Genet. May 10 [epub ahead of print] (PDF, 822 KB) Full Text
DeRosse P, Hodgkinson CA, Lencz T, et al. 2007. Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol. Psychiatry 61: 1208-1210.
Szeszko PR, Hodgkinson CA, Robinson DG, et al. 2007. DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia. Biol. Psychol. 2007 Nov 1. [Epub ahead of print]
Clapcote SJ, Lipina TV, Millar JK, et al. 2007. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387-402.
Clapcote SJ, Roder JC. 2006. <ahref="http://www.genetics.org/cgi/content/full/173/4/2407"target="_blank">Deletion polymorphism of Disc1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function.Genetics 173: 2407-2410. Full Text
Ishizuka K, Chen J, Taya S, et al. 2007. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol. Psychiatry 12: 897-899.
Akira Sawa, MD, PhD
Akira Sawa is associate professor in the Department of Neuroscience and the Department of Psychiatry and Behavioral Science, and director of the Program in Molecular Psychiatry at Johns Hopkins University School of Medicine. His lab conducts both basic and translational research into schizophrenia and other mood disorders, investigating the molecular pathogenesis of these psychiatric disturbances and seeking biomarkers and new molecular targets in human patients.
Sawa received his MD in 1990 and his PhD in 1994 from the University of Tokyo. From 1992 to 1996, he was a resident in neuropsychiatry at the same university. In 1996 he joined Johns Hopkins as a postdoctoral research fellow in the Sol Snyder lab, where he studied, among other things, the role of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and neurodegenerative disease.
Nicholas Brandon, PhD
Nicholas Brandon is currently head of neurobiology for Schizophrenia and Bipolar Research for Wyeth, based in Princeton. He is currently responsible for a group which looks to identify and characterize new targets for schizophrenia. Furthermore the group is looking to understand disease biology through extensive collaboration with academic partners including Akira Sawa's group at Johns Hopkins.
Brandon completed PhD and postdoctoral studies at University College London under the mentorship of Stephen Moss. His focus was on the regulation of the GABA-A receptor. In 2001 he joined Merck, where his group focused on schizophrenia biology, including DISC1 and DAO. He joined Wyeth in 2006. Current interests of his group include phosphodiesterases, DISC1, and estrogen biology.
Katherine E. Burdick, PhD
Katherine Burdick is currently the director of the Neurocognitive Assessment Laboratory in the Department of Psychiatry Research at the Zucker Hillside Hospital of the North Shore–LIJ Health System, and is an assistant professor at Albert Einstein School of Medicine and at CUNY–Queens College. Her primary area of interest is in neurocognitive function in patients with bipolar disorder. She has received a NARSAD Young Investigator Award and an NIMH K23 Career Development award to focus her work on familiality of neurocognitive deficits in bipolar disorder using a discordant sibling pair design. Burdick is also involved in a treatment trial funded by the Stanley Medical Research Institute, focused on pharmacological cognitive enhancement in patients with bipolar disorder. Other current research interests include the potential influence of susceptibility genes on neurocognitive function in patients with schizophrenia, affective illnesses, and healthy individuals.
Burdick received her undergraduate degree in psychology at the University of Rochester and her PhD in neuropsychology at the Graduate Center, City University of New York. She completed her clinical internship and postdoctoral work at Yale University School of Medicine.
Steven J. Clapcote, PhD
Steven Clapcote is Neurogenetics Project Leader in the School of Molecular and Clinical Medicine at the University of Edinburgh. Clapcote received his PhD from the University of Liverpool after studying the genetic basis of resistance to sleeping sickness in mice. He conducted postdoctoral research on the genetic basis of growth in mice under Chris Graham at the University of Oxford before receiving a Royal Society postdoctoral fellowship to obtain training in neurobiology under John Roder in the Centre for Neurodevelopment and Cognitive Function at Mount Sinai Hospital in Toronto, Canada. He will take up the position of lecturer in pharmacology at the University of Leeds in October 2008.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.