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


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.


CONCLUSIONS
We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia.
Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Itaru
I
Kushima
Yukako
Y
Nakamura
Branko
B
Aleksic
Masashi
M
Ikeda
Yoshihito
Y
Ito
Tomoko
T
Shiino
Tomo
T
Okochi
Yasuhisa
Y
Fukuo
Hiroshi
H
Ujike
Michio
M
Suzuki
Toshiya
T
Inada
Ryota
R
Hashimoto
Masatoshi
M
Takeda
Kozo
K
Kaibuchi
Nakao
N
Iwata
Norio
N
Ozaki
D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D036225:Receptor, EphB1 / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*
D020662:Guanine Nucleotide Exchange Factors; D036225:Receptor, EphB1; C503866:KALRN protein, human; D017346:Protein Serine-Threonine Kinases