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. The extremely high logarithm of odds (LOD) score of the chromosome-10 QTL suggests the presence of additional causative gene(s). Here, we reanalyzed the previously reported QTLs with increased marker density. The highest LOD 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. Therefore, we examined the roles of Cdh23 and c.753G>A in PPI. The Cdh23 gene was shown to be expressed in brain regions relevant for sensorimotor gating. We engineered the c.753G (C3H) allele into the B6 genetic background, which dampened PPI without affecting hearing acuity. An e-QTL (expression-QTL) effect imparted by the c.753G>A variant for the Cdh23 transcript in the brain was also revealed. The syntenous 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 data in the present study reveal a PPI-regulating Cdh23 variant and a possible contribution of this gene to schizophrenia susceptibility.
Competing Interest Statement
The authors have declared no competing interest.