Genetic architecture of the mouse hippocampus: identification of gene loci with selective regional effects

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Abstract
We recently mapped two quantitative trait loci that have widespread effects on hippocampal architecture in mouse:Hipp1aandHipp5a. We also noted remarkable strain differences in the relative sizes of different hippocampal regions. Estimated heritable variation for these differences was 42% in hippocampus proper, 40% in dentate gyrus, 31% in granule cell layer and 18% in pyramidal cell layer. Region size varied at least 50% from largest to smallest measurement. Here we have utilized these differences to identify loci with effects on the dentate gyrus, granule cell layer, hippocampus proper and pyramidal cell layer. Our sample consists of C57BL/6J and DBA/2J and 32 BXD recombinant inbred strains. Volumetric data were corrected for shrinkage and for differences in brain weight. We identified significant loci on chromosomes (Chr) 6, 13 and 15, and a significant interaction locus on proximal Chr 11. A suggestive distal Chr 1 locus overlaps withHipp1a. HipV13a(Chr 13, 42–78 Mb) has an additive effect of 0.56 mm3(12.1%) on dentate gyrus volume, whileGrV6a(Chr 6, 29–65 Mb) has additive effects of 0.14 mm3(16.0%) on the volume of the granule cell layer.HipV13aalso interacts withDGVi11a, a locus on proximal Chr 11 that operates exclusively through its epistatic effect onHipV13aand has no independent main effect.HipV15a(Chr 15, 0–51 Mb) has an additive effect of 1.76 mm3(9.0%) on the volume of the hippocampus proper. We used WebQTL, a recently described web‐based tool, to examine genetic correlation of gene expression with hippocampal volume. We identified a number of genes that map within the QTL intervals and have highly correlated expression patterns. Using WebQTL's extensive database of published BXD phenotypes, we also detected a strong and potentially biologically meaningful correlation between hippocampal volume and the acoustic startle response.