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Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory
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).
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