TY - JOUR
T1 - Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia
AU - Balan, Shabeesh
AU - Ohnishi, Tetsuo
AU - Watanabe, Akiko
AU - Ohba, Hisako
AU - Iwayama, Yoshimi
AU - Toyoshima, Manabu
AU - Hara, Tomonori
AU - Hisano, Yasuko
AU - Miyasaka, Yuki
AU - Toyota, Tomoko
AU - Shimamoto-Mitsuyama, Chie
AU - Maekawa, Motoko
AU - Numata, Shusuke
AU - Ohmori, Tetsuro
AU - Shimogori, Tomomi
AU - Kikkawa, Yoshiaki
AU - Hayashi, Takeshi
AU - Yoshikawa, Takeo
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.
AB - We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.
KW - Cdh23 (CDH23)
KW - hearing loss
KW - prepulse inhibition
KW - quantitative trait locus
KW - schizophrenia
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U2 - 10.1093/schbul/sbab007
DO - 10.1093/schbul/sbab007
M3 - Article
C2 - 33595068
AN - SCOPUS:85111164803
SN - 0586-7614
VL - 47
SP - 1190
EP - 1200
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 4
ER -
