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 - 01-05-2012

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Schizophrenia
Genes
Missense Mutation
Mutation
Genome-Wide Association Study
Oligonucleotide Array Sequence Analysis
Computer Simulation
Exons
Population

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

Cite this

Kushima, Itaru ; Nakamura, Yukako ; Aleksic, Branko ; Ikeda, Masashi ; Ito, Yoshihito ; Shiino, Tomoko ; Okochi, Tomo ; Fukuo, Yasuhisa ; Ujike, Hiroshi ; Suzuki, Michio ; Inada, Toshiya ; Hashimoto, Ryota ; Takeda, Masatoshi ; Kaibuchi, Kozo ; Iwata, Nakao ; Ozaki, Norio. / Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. In: Schizophrenia Bulletin. 2012 ; Vol. 38, No. 3. pp. 552-560.
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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.",
author = "Itaru Kushima and Yukako Nakamura and Branko Aleksic and Masashi Ikeda and Yoshihito Ito and Tomoko Shiino and Tomo Okochi and Yasuhisa Fukuo and Hiroshi Ujike and Michio Suzuki and Toshiya Inada and Ryota Hashimoto and Masatoshi Takeda and Kozo Kaibuchi and Nakao Iwata and Norio Ozaki",
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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, vol. 38, no. 3, pp. 552-560. https://doi.org/10.1093/schbul/sbq118

Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. / Kushima, Itaru; Nakamura, Yukako; Aleksic, Branko; Ikeda, Masashi; Ito, Yoshihito; Shiino, Tomoko; Okochi, Tomo; Fukuo, Yasuhisa; Ujike, Hiroshi; Suzuki, Michio; Inada, Toshiya; Hashimoto, Ryota; Takeda, Masatoshi; Kaibuchi, Kozo; Iwata, Nakao; Ozaki, Norio.

In: Schizophrenia Bulletin, Vol. 38, No. 3, 01.05.2012, p. 552-560.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility

AU - Kushima, Itaru

AU - Nakamura, Yukako

AU - Aleksic, Branko

AU - Ikeda, Masashi

AU - Ito, Yoshihito

AU - Shiino, Tomoko

AU - Okochi, Tomo

AU - Fukuo, Yasuhisa

AU - Ujike, Hiroshi

AU - Suzuki, Michio

AU - Inada, Toshiya

AU - Hashimoto, Ryota

AU - Takeda, Masatoshi

AU - Kaibuchi, Kozo

AU - Iwata, Nakao

AU - Ozaki, Norio

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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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DO - 10.1093/schbul/sbq118

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