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. 2014 Oct 3;15(1):850.
doi: 10.1186/1471-2164-15-850.

Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease

David G Ashbrook  1 , Robert W Williams, Lu Lu, Jason L Stein, Derrek P Hibar, Thomas E Nichols, Sarah E Medland, Paul M Thompson, Reinmar Hager
Affiliations

Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease

David G Ashbrook et al. BMC Genomics. .

Abstract

Background: Variation in hippocampal volume has been linked to significant differences in memory, behavior, and cognition among individuals. To identify genetic variants underlying such differences and associated disease phenotypes, multinational consortia such as ENIGMA have used large magnetic resonance imaging (MRI) data sets in human GWAS studies. In addition, mapping studies in mouse model systems have identified genetic variants for brain structure variation with great power. A key challenge is to understand how genetically based differences in brain structure lead to the propensity to develop specific neurological disorders.

Results: We combine the largest human GWAS of brain structure with the largest mammalian model system, the BXD recombinant inbred mouse population, to identify novel genetic targets influencing brain structure variation that are linked to increased risk for neurological disorders. We first use a novel cross-species, comparative analysis using mouse and human genetic data to identify a candidate gene, MGST3, associated with adult hippocampus size in both systems. We then establish the coregulation and function of this gene in a comprehensive systems-analysis.

Conclusions: We find that MGST3 is associated with hippocampus size and is linked to a group of neurodegenerative disorders, such as Alzheimer's.

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Figures

Figure 1
Figure 1
Quantile-quantile plot of human homologues of significant mouse genes for hippocampus size. For genes with a significant influence on hippocampus weight in mice (≤0.05) the significance of their influence on human hippocampus volume was plotted against a normal distribution of p-values. Although there are outliers, most of the points lie close to the y = x line, indicating there is no difference between what is seen in the data and what would be expected by chance. This is reinforced by the non-significant lambda value close to 1, which indicates no inflation of significance values.
See this image and copyright information in PMC

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