In Silico Whole Genome Association Scan for Murine Prepulse Inhibition

Authors

Bradley Todd Webb, Virginia Commonwealth UniversityFollow
Joseph L. McClay, Virginia Commonwealth UniversityFollow
Cristina Vargas-Irwin, Virginia Commonwealth University
Timothy P. York, Virginia Commonwealth UniversityFollow
Edwin J. C. G. van den Oord, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2009

Journal/Book/Conference Title

PLOS ONE

Volume

4

DOI of Original Publication

10.1371/journal.pone.0005246

Comments

Originally published at http://dx.doi.org/10.1371/journal.pone.0005246

Date of Submission

November 2014

Abstract

Background

The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups.

Methodology/Principal Findings

We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI.

Conclusions/Significance

These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.

Rights

© 2009 Webb et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Biomarker Research and Personalized Medicine Publications