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

Webb BT, McClay JL, Vargas-Irwin C, York TP, van den Oord EJ - PLoS ONE (2009)

Bottom Line: 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.These genes also appear to have correlated expression with PPI.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA. btwebb@vcu.edu

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.

Show MeSH

Related in: MedlinePlus

Plot of p-values from PPI scan across mouse genome with corresponding FDR thresholds.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2666808&req=5

pone-0005246-g001: Plot of p-values from PPI scan across mouse genome with corresponding FDR thresholds.

Mentions: Our base model was a 2-level model where mice were nested in strains with sex and clade membership included as covariates. SNPs were added to this base model and tests performed to examine whether this significantly improved model fit. Figure 1 plots the p-values for all SNPs across the mouse genome. The conservative “lowest slope” method (Hsueh et al., 2003) estimated the proportion of true hypotheses to be 0.991017. Using this estimate, we found 89 significant SNPs when the FDR was controlled at the 0.05 level. Because of the large number of tests, this means that the estimated proportion of false discoveries among the 89 significant tests was 5%. The number of significant SNPs dropped noticeably from 89 to 20 when the FDR was controlled at the 0.045 rather than 0.05 level, which corresponded with a threshold p-value of 5.0e-5. We focused these SNPs in order to have tractable number of results to interpret. The full list of results satisfying a FDR of 5% are contained in Table S1.


In silico whole genome association scan for murine prepulse inhibition.

Webb BT, McClay JL, Vargas-Irwin C, York TP, van den Oord EJ - PLoS ONE (2009)

Plot of p-values from PPI scan across mouse genome with corresponding FDR thresholds.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2666808&req=5

pone-0005246-g001: Plot of p-values from PPI scan across mouse genome with corresponding FDR thresholds.
Mentions: Our base model was a 2-level model where mice were nested in strains with sex and clade membership included as covariates. SNPs were added to this base model and tests performed to examine whether this significantly improved model fit. Figure 1 plots the p-values for all SNPs across the mouse genome. The conservative “lowest slope” method (Hsueh et al., 2003) estimated the proportion of true hypotheses to be 0.991017. Using this estimate, we found 89 significant SNPs when the FDR was controlled at the 0.05 level. Because of the large number of tests, this means that the estimated proportion of false discoveries among the 89 significant tests was 5%. The number of significant SNPs dropped noticeably from 89 to 20 when the FDR was controlled at the 0.045 rather than 0.05 level, which corresponded with a threshold p-value of 5.0e-5. We focused these SNPs in order to have tractable number of results to interpret. The full list of results satisfying a FDR of 5% are contained in Table S1.

Bottom Line: 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.These genes also appear to have correlated expression with PPI.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA. btwebb@vcu.edu

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.

Show MeSH
Related in: MedlinePlus