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Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory
Open accessAbstract
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.
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“loss-of-function translocations in DISC1 are associated with high rates of mental illness129, and with reduced PFC grey matter and impaired working memory in patients with schizophrenia130.”
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“Mutations in DISC1 are associated with high rates of mental illness120,121, and more subtle polymorphisms are associated with decreased PFC gray matter and impaired working memory122,123.”
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Metadata
- Authors
- Cannon, T. D., Hennah, W., van Erp, T. G. M., Thompson, P. M., Lonnqvist, J., Huttunen, M., Gasperoni, T., Tuulio-Henriksson, A., Pirkola, T., Toga, A. W., Kaprio, J., Mazziotta, J., & Peltonen, L.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2005-11-01
- Volume
- 62
- Issue
- 11
- Pages
- 1205
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2117644711
- Cited by
- 337
- References
- 64
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 14 · 2015: 19 · 2014: 8 · 2013: 14 · 2012: 24
- FWCI
- 21.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH-52857, R01MH052857)
- National Institute of Biomedical Imaging and Bioengineering (R21EB001561, EB01561)
- National Center for Research Resources (P41RR013642, R21RR019771, RR 13642, RR 19771, RR00827, M01RR000827)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, DISC1, TRAX, haplotype association, genetic susceptibility, short-term memory, long-term memory, hippocampal volume, endophenotypes, monozygotic twins, dizygotic twins, single nucleotide polymorphisms, brain structure, synaptogenesis
- MeSH terms
- Atrophy, Diseases in Twins, DNA-Binding Proteins, Female, Finland, Haplotypes, Humans, Magnetic Resonance Imaging, Male, Memory Disorders, Middle Aged, Nerve Tissue Proteins, Neuropsychological Tests, Phenotype, Risk Factors, Schizophrenia, Twins, Dizygotic, Twins, Monozygotic, Cohort Studies, Prefrontal Cortex, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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