Resequencing and Association Analysis of the KALRN and EPHB1 Genes And Their Contribution to Schizophrenia Susceptibility
Open accessAbstract
BACKGROUND: Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) in KALRN or EPHB1. METHODS AND RESULTS: The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. CONCLUSION: We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia.
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Several missense mutations in KALRN have been identified in schizophrenia, occur in conserved regions, and are predicted to have functional consequences.
“Recently, several missense mutations in the KALRN gene were identified in schizophrenia. These mutations occurred in evolutionary conserved gene regions and are predicted to have functional consequences57.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [57]
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- Authors
- Kushima, I., Nakamura, Y., Aleksic, B., Ikeda, M., Ito, Y., Shiino, T., Okochi, T., Fukuo, Y., Ujike, H., Suzuki, M., Inada, T., Hashimoto, R., Takeda, M., Kaibuchi, K., Iwata, N., & Ozaki, N.
- Affiliations
- Japan Science and Technology Agency (JP)
- Fujita Health University (JP)
- Okayama University (JP)
- Seiwa Hospital (JP)
- Kanazawa University (JP)
- Corresponding author
- Iwata, Nakao
- ORCID
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-11-01
- Volume
- 38
- Issue
- 3
- Pages
- 552-560
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC3329972
- OpenAlex
- W2143523145
- Cited by
- 92
- References
- 37
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 3 · 2015: 6 · 2014: 9 · 2013: 7 · 2012: 9
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Schizophrenia Bulletin (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Nagoya University Repository (NAGOYA Repository) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (22390225, 23659565, 23659563, 22390223)
- Core Research for Evolutional Science and Technology
- 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, KALRN
- MeSH terms
- Adult, Exons, Female, Genotype, Humans, Japan, Male, Middle Aged, Risk Factors, Schizophrenia, Protein Serine-Threonine Kinases, Genetic Predisposition to Disease, Mutation, Missense, Guanine Nucleotide Exchange Factors, Receptor, EphB1, Genome-Wide Association Study
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