In silico whole genome association scan for murine prepulse inhibition.
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.


RESULTS
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
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.
Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA. btwebb@vcu.edu
Bradley Todd
BT
Webb
Joseph L
JL
McClay
Cristina
C
Vargas-Irwin
Timothy P
TP
York
Edwin J C G
EJ
van den Oord
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D002896:Chromosomes, Human, Pair 6; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D015870:Gene Expression; D005796:Genes; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D008815:Mice, Inbred Strains; D009433:Neural Inhibition / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D012559:Schizophrenia / Q000235:genetics
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C095563:TSN protein, human