Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility

Itaru Kushima, Yukako Nakamura, Branko Aleksic, Masashi Ikeda, Yoshihito Ito, Tomoko Shiino, Tomo Okochi, Yasuhisa Fukuo, Hiroshi Ujike, Michio Suzuki, Toshiya Inada, Ryota Hashimoto, Masatoshi Takeda, Kozo Kaibuchi, Nakao Iwata, Norio Ozaki

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Abstract

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.

Original languageEnglish
Pages (from-to)552-560
Number of pages9
JournalSchizophrenia Bulletin
Volume38
Issue number3
DOIs
Publication statusPublished - 05-2012

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

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    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. (2012). Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. Schizophrenia Bulletin, 38(3), 552-560. https://doi.org/10.1093/schbul/sbq118