Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.

[1]  G. McCloskey.  Wide Range Achievement Test-Revised , 1987 .

[2]  D. Clair,et al.  Association within a family of a balanced autosomal translocation with major mental illness , 1990, The Lancet.

[3]  Robert Freedman,et al.  Elementary neuronal dysfunctions in schizophrenia , 1991, Schizophrenia Research.

[4]  T. Goldberg,et al.  Learning and memory in monozygotic twins discordant for schizophrenia , 1993, Psychological Medicine.

[5]  Jeffrey A. Lieberman,et al.  Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia , 1995, Schizophrenia Research.

[6]  G Tedeschi,et al.  Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. , 1996, The American journal of psychiatry.

[7]  Karl J. Friston,et al.  Nonlinear Regression in Parametric Activation Studies , 1996, NeuroImage.

[8]  T. Matise,et al.  Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium. , 1998, American journal of medical genetics.

[9]  S. Faraone,et al.  Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands , 1998, Psychiatry Research.

[10]  W. Ewens,et al.  A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. , 1998, American journal of human genetics.

[11]  Michael D. Nelson,et al.  Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging : A meta-analytic study , 1998 .

[12]  D. Munoz,et al.  Contributions of the entorhinal cortex, amygdala and hippocampus to human memory , 1998, Neuropsychologia.

[13]  N. Alpert,et al.  Impaired recruitment of the hippocampus during conscious recollection in schizophrenia , 1998, Nature Neuroscience.

[14]  R. Coppola,et al.  Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. , 1999, Cerebral cortex.

[15]  D. Clayton,et al.  A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. , 1999, American journal of human genetics.

[16]  D. Weinberger,et al.  Cell biology of the hippocampal formation in schizophrenia , 1999, Biological Psychiatry.

[17]  K. Livak,et al.  Allelic discrimination using fluorogenic probes and the 5' nuclease assay. , 1999, Genetic analysis : biomolecular engineering.

[18]  Gonçalo R. Abecasis,et al.  GOLD-Graphical Overview of Linkage Disequilibrium , 2000, Bioinform..

[19]  M. Egan,et al.  Relative risk of attention deficits in siblings of patients with schizophrenia. , 2000, The American journal of psychiatry.

[20]  K. Weiss,et al.  How many diseases does it take to map a gene with SNPs? , 2000, Nature Genetics.

[21]  Martin S. Taylor,et al.  Disruption of two novel genes by a translocation co-segregating with schizophrenia. , 2000, Human molecular genetics.

[22]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[23]  Karl J. Friston,et al.  A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains , 2001, NeuroImage.

[24]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[26]  D J Porteous,et al.  Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. , 2001, American journal of human genetics.

[27]  Michael F Egan,et al.  Relative risk for cognitive impairments in siblings of patients with schizophrenia , 2001, Biological Psychiatry.

[28]  D. Blackwood,et al.  Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder , 2001, Psychiatric genetics.

[29]  S. Snyder,et al.  Disrupted-in-Schizophrenia-1 (DISC-1): Mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[31]  M. Egan,et al.  Serotonin Transporter Genetic Variation and the Response of the Human Amygdala , 2002, Science.

[32]  Akira Sawa,et al.  Schizophrenia: Diverse Approaches to a Complex Disease , 2002, Science.

[33]  C. Austin,et al.  Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). , 2002, Genomics.

[34]  M. Egan,et al.  Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance , 2003, The Journal of Neuroscience.

[35]  M Tohyama,et al.  Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth , 2003, Molecular Psychiatry.

[36]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[37]  M. Egan,et al.  Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. , 2003, The American journal of psychiatry.

[38]  Martin S. Taylor,et al.  Evolutionary constraints on the Disrupted in Schizophrenia locus. , 2003, Genomics.

[39]  Leena Peltonen,et al.  Genetic linkage and association between chromosome 1q and working memory function in schizophrenia , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[40]  Christopher P Austin,et al.  DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. , 2003, Human molecular genetics.

[41]  Leena Peltonen,et al.  Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. , 2003, Human molecular genetics.

[42]  M. Egan,et al.  Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. , 2003, The American journal of psychiatry.

[43]  C. Austin,et al.  DISC1 (Disrupted in Schizophrenia‐1) is expressed in limbic regions of the primate brain , 2003, Neuroreport.

[44]  A. Meyer-Lindenberg,et al.  Interindividual differences in functional interactions among prefrontal, parietal and parahippocampal regions during working memory. , 2003, Cerebral cortex.

[45]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.

[46]  David Goldman,et al.  Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. , 2004, American journal of human genetics.

[47]  A. Meyer-Lindenberg,et al.  The Brain-derived Neurotrophic Factor Val66met Polymorphism and Variation in Human Cortical Morphology , 2022 .

[48]  W Hennah,et al.  Replication of 1q42 linkage in Finnish schizophrenia pedigrees , 2004, Molecular Psychiatry.

[49]  C. Austin,et al.  Expression of disrupted-in-schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development , 2004, Neuroscience.