This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (97)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Neurology  • Neurogenetics  • Schizophrenia  • Alert me on articles by topic  Social Bookmarking   What's this?

Tyrone D. Cannon, PhD; William Hennah, MA; Theo G. M. van Erp, MA; Paul M. Thompson, PhD; Jouko Lonnqvist, MD, PhD; Matti Huttunen, MD, PhD; Timothy Gasperoni, PhD; Annamari Tuulio-Henriksson, PhD; Tia Pirkola, MA; Arthur W. Toga, PhD; Jaakko Kaprio, MD, PhD; John Mazziotta, MD, PhD; Leena Peltonen, MD, PhD

Arch Gen Psychiatry. 2005;62:1205-1213.

Context  Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified.

Objective  To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis.

Design  Population-based twin cohort study.

Setting  Finland.

Participants  Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and 1 dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957.

Main Outcome Measures  Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images.

Results  A common haplotype incorporating 3 single-nucleotide 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 short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume.

Conclusions  Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.

Author Affiliations: Departments of Psychology, Psychiatry and Biobehavioral Sciences (Drs Cannon and Gasperoni and Mr van Erp) and Laboratory of Neuroimaging and Ahmanson-Lovelace Brain Mapping Center (Drs Thompson, Toga, and Mazziotta), University of California–Los Angeles; Departments of Molecular Medicine (Mr Hennah and Dr Peltonen) and Mental Health and Alcohol Research (Drs Lonnqvist, Huttunen, Tuulio-Henriksson, and Kaprio and Ms Pirkola), National Public Health Institute, Helsinki, Finland; and Department of Public Health, University of Helsinki, Helsinki (Dr Kaprio).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Time-Lapse Mapping of Cortical Changes in Schizophrenia with Different Treatments
Thompson et al.
Cereb Cortex 2009;19:1107-1123.
ABSTRACT | FULL TEXT  

Association of Variants in DISC1 With Psychosis-Related Traits in a Large Population Cohort
Tomppo et al.
Arch Gen Psychiatry 2009;66:134-141.
ABSTRACT | FULL TEXT  

Morphometric Brain Abnormalities in Schizophrenia in a Population-Based Sample: Relationship to Duration of Illness
Tanskanen et al.
Schizophr Bull 2008;0:sbn141v1-sbn141.
ABSTRACT | FULL TEXT  

Heritability of Changes in Brain Volume Over Time in Twin Pairs Discordant for Schizophrenia
Brans et al.
Arch Gen Psychiatry 2008;65:1259-1268.
ABSTRACT | FULL TEXT  

Gene-Environment Interaction and Covariation in Schizophrenia: The Role of Obstetric Complications
Mittal et al.
Schizophr Bull 2008;34:1083-1094.
ABSTRACT | FULL TEXT  

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing Truncated Disc1
Shen et al.
J. Neurosci. 2008;28:10893-10904.
ABSTRACT | FULL TEXT  

Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: Evidence of epistasis and competitive binding
Burdick et al.
Hum Mol Genet 2008;17:2462-2473.
ABSTRACT | FULL TEXT  

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness
Hains and Arnsten
Learn. Mem. 2008;15:551-564.
ABSTRACT | FULL TEXT  

Structural Cerebral Variations as Useful Endophenotypes in Schizophrenia: Do They Help Construct "Extended Endophenotypes"?
Prasad and Keshavan
Schizophr Bull 2008;34:774-790.
ABSTRACT | FULL TEXT  

Imaging Genetics of Brain Longevity and Mental Wellness: The Next Frontier?
Petrella et al.
Radiology 2008;246:20-32.
ABSTRACT | FULL TEXT  

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice
Li et al.
Proc. Natl. Acad. Sci. USA 2007;104:18280-18285.
ABSTRACT | FULL TEXT  

Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments
Palo et al.
Hum Mol Genet 2007;16:2517-2528.
ABSTRACT | FULL TEXT  

From the Cover: Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans
Hikida et al.
Proc. Natl. Acad. Sci. USA 2007;104:14501-14506.
ABSTRACT | FULL TEXT  

Neuroimaging and other neurobiological indices in schizophrenia: relationship to measurement of functional outcome
Waddington
Br. J. Psychiatry 2007;191:s52-s57.
ABSTRACT | FULL TEXT  

Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1
Hennah et al.
Hum Mol Genet 2007;16:453-462.
ABSTRACT | FULL TEXT  

Schizophrenia: a common disease caused by multiple rare alleles
McClellan et al.
Br. J. Psychiatry 2007;190:194-199.
ABSTRACT | FULL TEXT  

Allelic Variation in RGS4 Impacts Functional and Structural Connectivity in the Human Brain
Buckholtz et al.
J. Neurosci. 2007;27:1584-1593.
ABSTRACT | FULL TEXT  

Deconstructing Schizophrenia: An Overview of the Use of Endophenotypes in Order to Understand a Complex Disorder
Braff et al.
Schizophr Bull 2007;33:21-32.
ABSTRACT | FULL TEXT  

The Consortium on the Genetics of Schizophrenia: Neurocognitive Endophenotypes
Gur et al.
Schizophr Bull 2007;33:49-68.
ABSTRACT | FULL TEXT  

DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1
Kamiya et al.
Hum Mol Genet 2006;15:3313-3323.
ABSTRACT | FULL TEXT  

Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
Hashimoto et al.
Hum Mol Genet 2006;15:3024-3033.
ABSTRACT | FULL TEXT  

A Tail of Two Signals: The C Terminus of the A2A-Adenosine Receptor Recruits Alternative Signaling Pathways
Gsandtner and Freissmuth
Mol. Pharmacol. 2006;70:447-449.
ABSTRACT | FULL TEXT  

Deletion Polymorphism of Disc1 Is Common to All 129 Mouse Substrains: Implications for Gene-Targeting Studies of Brain Function
Clapcote and Roder
Genetics 2006;173:2407-2410.
ABSTRACT | FULL TEXT  

Genes and Schizophrenia: Beyond Schizophrenia: The Role of DISC1 in Major Mental Illness
Hennah et al.
Schizophr Bull 2006;32:409-416.
ABSTRACT | FULL TEXT  

Chromosomal abnormalities and psychosis
MUIR et al.
Br. J. Psychiatry 2006;188:501-503.
ABSTRACT | FULL TEXT  

Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs
Lipska et al.
Hum Mol Genet 2006;15:1245-1258.
ABSTRACT | FULL TEXT  

Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice
Koike et al.
Proc. Natl. Acad. Sci. USA 2006;103:3693-3697.
ABSTRACT | FULL TEXT