Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia

• Published in: Schizophrenia bulletin Vol. 47; no. 4; pp. 1190 - 1200
• Main Authors: Balan, Shabeesh, Ohnishi, Tetsuo, Watanabe, Akiko, Ohba, Hisako, Iwayama, Yoshimi, Toyoshima, Manabu, Hara, Tomonori, Hisano, Yasuko, Miyasaka, Yuki, Toyota, Tomoko, Shimamoto-Mitsuyama, Chie, Maekawa, Motoko, Numata, Shusuke, Ohmori, Tetsuro, Shimogori, Tomomi, Kikkawa, Yoshiaki, Hayashi, Takeshi, Yoshikawa, Takeo
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 08.07.2021
• Subjects: Alleles; Animals; Cadherin Related Proteins - genetics; Cadherins - genetics; Humans; Mice; Prepulse Inhibition - genetics; Quantitative Trait Loci; Regular; Schizophrenia - genetics; (; quantitative trait locus; ); prepulse inhibition; schizophrenia; hearing loss; Cdh23 (CDH23)
• ISSN: 0586-7614; 1745-1701
• DOI: 10.1093/schbul/sbab007

Abstract 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.