Fine mapping of QTL for prepulse inhibition in LG/J and SM/J mice using F(2) and advanced intercross lines

Abstract

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating, a process that filters out extraneous sensory, motor and cognitive information. Humans with neurological and psychiatric disorders, including schizophrenia, obsessive-compulsive disorder and Huntington's disease, exhibit a reduction in PPI. Habituation of the startle response is also disrupted in schizophrenic patients. In order to elucidate the genes involved in sensorimotor gating, we phenotyped 472 mice from an F(2) cross between LG/J × SM/J for PPI and genotyped these mice genome-wide using 162 single nucleotide polymorphism (SNP) markers. We used prepulse intensity levels that were 3, 6 and 12 dB above background (PPI3, PPI6 and PPI12, respectively). We identified a significant quantitative trait locus (QTL) on chromosome 12 for all three prepulse intensities as well as a significant QTL for both PPI6 and PPI12 on chromosome 11. We identified QTLs on chromosomes 7 and 17 for the startle response when sex was included as an interactive covariate and found a QTL for habituation of the startle response on chromosome 4. We also phenotyped 135 mice from an F(34) advanced intercross line (AIL) between LG/J × SM/J for PPI and genotyped them at more than 3000 SNP markers. Inclusions of data from the AIL mice reduced the size of several of these QTLs to less than 5 cM. These results will be useful for identifying genes that influence sensorimotor gaiting and show the power of AIL for fine mapping of QTLs.

Figure 1. Sex and strain differences in startle, PPI and habituation

We observed significant differences between the strains for startle and PPI; however, there was no significant difference between the two strains for habituation. There was a significant interaction between strain and sex for startle but not for any of the other traits. Startle and habituation are both expressed in arbitrary units. # and * indicate differences between the two strains with P < 0.05 and P < 0.001, respectively.

Figure 2. Genome-wide LOD scores for startle show a significant peak on chromosomes 7 and 17 in the F₂ generation when sex was treated as an interactive covariate

The effect plot of each genotype at the marker nearest to the peak LOD score (indicated with a heavy tick mark) is shown for markers rs31102161 and rs29530504. The horizontal line indicates the genome-wide significance threshold (P < 0.05). Startle response is in arbitrary units.

Figure 3. LOD scores for all three PPI intensities on chromosomes 11 and 12 based on analysis of the F₂ mice

The mean phenotype for mice with the indicated genotypes at the marker closest to the peak LOD score for chromosomes 11 and 12 are shown in the lower right. Horizontal lines indicate the genome-wide significance thresholds (P < 0.05).

Figure 4. LOD scores for habituation show a significant peak on chromosome 4 in the F₂ generation

The plot in the lower right shows the mean phenotype associated with each genotype at the marker nearest to the peak LOD score. The horizontal line indicates the genome-wide significance threshold (P < 0.05). Habituation is expressed as the difference between the first six and the last six startle alone trials, in arbitrary units.

Figure 5. Integrated analysis of F₂ and AIL for startle, PPI and habituation

LOD scores are shown on the y-axis and genetic distance in cM is plotted on the x-axis. Horizontal lines indicate the genome-wide significance thresholds (P < 0.05).