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

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.

SUBMITTER: Kushima I

PROVIDER: S-EPMC3329972 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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

Kushima Itaru I Nakamura Yukako Y Aleksic Branko B Ikeda Masashi M Ito Yoshihito Y Shiino Tomoko T Okochi Tomo T Fukuo Yasuhisa Y Ujike Hiroshi H Suzuki Michio M Inada Toshiya T Hashimoto Ryota R Takeda Masatoshi M Kaibuchi Kozo K Iwata Nakao N Ozaki Norio N

Schizophrenia bulletin 20101101 3

<h4>Background</h4>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 ...[more]

PMID: 21041834

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Dataset Information

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

Publications

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

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