Haplotype and Expression Mapping of Prepulse Inhibition

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DESCRIPTION (provided by applicant): Prepulse inhibition of startle (PPI) is a neurophysiological trait that is impaired in schizophrenia patients and varies among inbred mouse strains. We have studied chromosome substitution mouse strains (consomic strains) derived from C57BL/6J and A/J mice to identify chromosomes that harbor PPI quantitative trait loci (QTLs), and have obtained evidence for one or more PPI genes on mouse chromosome 16. Since our original application, we have rapidly completed intercross mapping, allowing us to identify two significant PPI QTLs on chromosome 16 (LODs = 3.9 and 4.6) that are 3.5 cM and 5.5 cM in size. We propose to identify the mouse chromosome 16 PPI genes using a multi-faceted approach that incorporates inbred strain haplotype mapping and mRNA expression profiling. We will first refine the chromosome 16 QTLs using haplotype mapping across multiple inbred mouse strains known to vary in PPI. In parallel, we will perform backcrosses of mice segregating each chromosome 16 QTL and test recombinant inbred strains for PPI to assist in refining the loci. We will then perform mRNA expression studies of relevant brain regions in the C57BL/6J and chromosome 16 substitution strains to identify differentially expressed genes as candidate PPI genes. These data will be translated into the human studies ongoing in our lab to determine whether the orthologs of the candidate mouse PPI genes are involved in human PPI or schizophrenia risk. We will carry out this aim by constructing human haplotype maps of candidate PPI genes identified by mapping and profiling, and then testing for association with schizophrenia and PPI in our patient samples. This proposal is a pilot study to identify genes involved in PPI and perhaps schizophrenia, and is also a proof-of-principle that this multi-faceted approach could be widely applicable to the study of complex human traits.