Association of DISC 1 / TRAX Haplotypes With Schizophrenia , Reduced Prefrontal Gray Matter , and Impaired Short-and Long-term Memory

Results: A common haplotype incorporating 3 singlenucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P=.02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P=.001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in shortand long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a populationbased brain atlas method, with a trend toward association with reduced hippocampal volume.

[1]  Jacob Cohen.  A Coefficient of Agreement for Nominal Scales , 1960 .

[2]  Elbert W. Russell,et al.  A multiple scoring method for the assessment of complex memory functions. , 1975 .

[3]  M. Schlossberg.  The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. , 1986 .

[4]  P. McGuffin,et al.  Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition. , 1987, Archives of general psychiatry.

[5]  P S Goldman-Rakic,et al.  Activation of the hippocampus and dentate gyrus by working-memory: a 2- deoxyglucose study of behaving rhesus monkeys , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[7]  C. Dodrill,et al.  Reliability of the Lateral Dominance Examination. , 1993, Journal of clinical and experimental neuropsychology.

[8]  Alan C. Evans,et al.  Multiple surface identification and matching in magnetic resonance images , 1994, Other Conferences.

[9]  B M Dawant,et al.  Brain segmentation and white matter lesion detection in MR images. , 1994, Critical reviews in biomedical engineering.

[10]  Tyrone D. Cannon,et al.  Attentional dysfunctions in neuroleptic-naive and neuroleptic-withdrawn schizophrenic patients and their siblings , 1995, Schizophrenia Research.

[11]  J. Vilkki,et al.  Dual task performance after focal cerebral lesions and closed head injuries , 1996, Neuropsychologia.

[12]  P. Goldman-Rakic.  Regional and cellular fractionation of working memory. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Paul M. Thompson,et al.  Detection, visualization and animation of abnormal anatomic structure with a deformable probabilistic brain atlas based on random vector field transformations , 1997, Medical Image Anal..

[14]  L. Squire,et al.  Episodic memory, semantic memory, and amnesia , 1998, Hippocampus.

[15]  K. Weiss,et al.  Linkage disequilibrium mapping of complex disease: fantasy or reality? , 1998, Current opinion in biotechnology.

[16]  Tyrone D. Cannon,et al.  The genetic epidemiology of schizophrenia in a Finnish twin cohort. A population-based modeling study. , 1998, Archives of general psychiatry.

[17]  A. Toga,et al.  In vivo evidence for post-adolescent brain maturation in frontal and striatal regions , 1999, Nature Neuroscience.

[18]  D. Henze,et al.  Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex. , 2000, Journal of neurophysiology.

[19]  Tyrone D. Cannon,et al.  The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. , 2000, American journal of human genetics.

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

[21]  G. Abecasis,et al.  A general test of association for quantitative traits in nuclear families. , 2000, American journal of human genetics.

[22]  D. Lewis,et al.  Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. , 2000, Archives of general psychiatry.

[23]  J. Suvisaari,et al.  Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. , 2000, Human molecular genetics.

[24]  J. Baraban,et al.  Somatodendritic Localization of Translin, a Component of the Translin/Trax RNA Binding Complex , 2000, Journal of neurochemistry.

[25]  D. Porteous,et al.  Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. , 2000, Genomics.

[26]  R. Woods,et al.  Cortical change in Alzheimer's disease detected with a disease-specific population-based brain atlas. , 2001, Cerebral cortex.

[27]  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.

[28]  J S Sinsheimer,et al.  Chromosome 1 loci in Finnish schizophrenia families. , 2001, Human molecular genetics.

[29]  Tyrone D. Cannon,et al.  Genetic influences on brain structure , 2001, Nature Neuroscience.

[30]  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.

[31]  Tyrone D. Cannon,et al.  Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. V. Van Heertum,et al.  Prefrontal Dopamine D1 Receptors and Working Memory in Schizophrenia , 2002, The Journal of Neuroscience.

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

[34]  Charles R Cantor,et al.  Automated genotyping using the DNA MassArray technology. , 2002, Methods in molecular biology.

[35]  H. Pétursson,et al.  Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23‐q24, and suggests the presence of additional loci on 1p and 1q , 2003, Psychiatric genetics.

[36]  C. Sabatti,et al.  The Human Phenome Project , 2003, Nature Genetics.

[37]  M Tohyama,et al.  Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth , 2003, Molecular 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]  H. Hwu,et al.  Linkage of schizophrenia with chromosome 1q loci in Taiwanese families , 2003, Molecular Psychiatry.

[41]  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.

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

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

[44]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[45]  Inah Lee,et al.  Differential roles of dorsal hippocampal subregions in spatial working memory with short versus intermediate delay. , 2003, Behavioral neuroscience.

[46]  Tyrone D. Cannon,et al.  Hippocampal volumes in schizophrenic twins , 2003, Schizophrenia Research.

[47]  Michael J Owen,et al.  Recent advances in the genetics of schizophrenia. , 2003, Human molecular genetics.

[48]  P. Visscher,et al.  A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42 , 2004, Molecular Psychiatry.

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

[50]  N. Brandon,et al.  DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness , 2004, Annals of medicine.

[51]  Thessa T. J. P. Kockelkorn,et al.  Association study of polymorphisms in the 5′ upstream region of human DISC1 gene with schizophrenia , 2004, Neuroscience Letters.

[52]  Tyrone D. Cannon,et al.  Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. , 2004, Human molecular genetics.

[53]  R James,et al.  Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria , 2004, Molecular and Cellular Neuroscience.

[54]  Eran Halperin,et al.  Haplotype reconstruction from genotype data using Imperfect Phylogeny , 2004, Bioinform..

[55]  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.

[56]  C. Ross,et al.  A form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  N. Andreasen.  Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) 1982 , 2007 .