Ashbrook, David G., Williams, Robert W., Lu, Lu, Stein, Jason L., Hibar, Derrek P., Nichols, Thomas E., Medland, Sarah E., Thompson, Paul M. and Hager, Reinmar (2014) Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genomics, Volume 15 (Number 1). Article number 850. doi:10.1186/1471-2164-15-850 ISSN 1471-2164.

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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.

Keywords: Comparative analysis; Hippocampus; MGST3; BXD
Background
The hippocampus is a key forebrain region involved in declarative memory, cognition, and spatial navigation. Hippocampal volume is highly variable with unilateral values ranging from ~2500 to 5000 mm3 among healthy young humans (mean 3,917 mm3, s.d. = 441 mm3) and from 15.2 to 23.0 mm3 among young adult mice [1,2]. Heritability ranges from 40% to 70% in both species [3,4], and a small fraction of the difference in volume is also attributable to sex [4,5]. This wide range of natural variation raises the possibility that susceptibility to a subset of neurodegenerative and psychiatric disorders linked to defects in the hippocampus may depend, in part, on its initial healthy volume. Individuals who develop and retain a large hippocampus into adulthood may be comparatively resistant to some forms of disease, particularly Alzheimer’s. Such a "reserve" hypothesis of neurological disease [6,7] has been proposed for Parkinson’s [8], Huntington’s [9] and Alzheimer’s [10] diseases. Lower than average volume has been linked to a number of disorders [11] including depression [12-16], Alzheimer’s disease [17] and schizophrenia [18]. Understanding the genetic factors that contribute to individual differences in hippocampal volume is thus crucial in providing insight into vulnerability and severity of disease.

Prior efforts to identify genetic variants underlying differences in brain structure have used large data sets in human genome-wide association studies (GWAS) or extensive mapping populations in mouse model systems. GWAS in humans typically have modest statistical power due to high corrections needed to compensate for multiple testing. However, loci are defined with very high precision, often down to the level of single nucleotide polymorphisms (SNPs). In contrast, mouse linkage studies often have high statistical power to detect genetic effects but lower genetic resolution, producing loci that include hundreds of genes [19,20]. Combining data from mice and humans overcomes some of these problems, gaining power from mouse crosses and precision from human GWAS. This method also ensures the translational relevance, giving confidence to the human results, as the same gene controlling the same phenotype is found in a related species. Further, this approach illustrates that the homologous mouse gene is relevant to the human phenotype, as well as the significance of experimental research in model systems that would not be possible in humans. Homologous genes are genes that share a common evolutionary ancestor. In this study we are specifically looking at a subset of homologous genes, orthologs, which derive from a speciation event, rather than paralogs, which arise because of a gene duplication event.

This study takes a cross-species approach to identify genes with an evolutionarily conserved role in influencing hippocampus size; i.e. because a given gene is playing the same role in two different species we hypothesize that it was playing the same role in the ancestral species. Previous studies have begun to show the utility of using a cross-species approach to identify genes underlying a phenotype of interest [21-25]. This approach has the advantage that it allows the investigation of disease phenotypes without requiring data from experimental perturbations. Instead we utilize data obtained from populations that segregated for large numbers of common sequence variants and associated differences in phenotype.

Here, we use data from the largest mouse model system, BXD, to identify a set of genes associated with hippocampus size in a joint analysis with human hippocampus MRI data obtained by the ENIGMA consortium for GWAS [26]. We identify, MGST3 [Entrez: 4259] and use a systems-genetics approach that links this gene to neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.

Results
Identification of genes significant in both species
Associations between genes and hippocampus size in BXD mice were estimated using p-values for over 3800 markers obtained for QTL interval mapping. QTL mapping identifies a region of the genome significantly linked to variation in the phenotype. Having identified QTL, we then estimated a particular gene’s significance based on its base pair distance from the nearest two markers and the significance of these two markers. Therefore any particular gene will have a p-value somewhere between the p-values of its two closest markers. The next step in our analysis was to obtain SNP level p-values for association with human hippocampus volume, which were converted to gene p-values to allow comparison with data for the mouse hippocampus. Using the SNP p-values from the human GWAS, the Versatile Gene-based Association Study (VEGAS) website [27] produced gene p-values for a total of 17,787 human genes. Secondly, the mouse homologues of these human genes were identified and yielded a total of 15,705 genes (88.3% of the human genes).

Using a relaxed (i.e. uncorrected) p-value of ≤ 0.05, 1015 human genes (916 with mouse homologues; 90.2%) were then nominally identified as having an effect on hippocampus size. Overall, there is no indication that the significance of any given gene with the entire region identified in the QTL analysis of BXD mouse hippocampus weight is indicative of the homologous gene’s significance on human hippocampus volume, as judged by the quantile-quantile plot and lambda (λ = 0.912, p = 0.82; Figure 1). This is corroborated by a separate Rank Rank Hypergeometric Overlap test [28] used to compare the two datasets, which yielded a non-significant result (p = 0.38, corrected by the familywise error rate). This is unsurprising as a QTL analysis identifies a region of the genome associated with a trait, and therefore in our analysis all genes within the mouse QTL were significant. However, not all the genes within a QTL contribute to the phenotype, but only a subset or even a single gene.

Item Type:	Journal Article
Divisions:	Faculty of Science, Engineering and Medicine > Science > Statistics
Journal or Publication Title:	BMC Genomics
Publisher:	BioMed Central Ltd.
ISSN:	1471-2164
Official Date:	3 October 2014
Dates:	Date Event 3 October 2014 Published 29 September 2014 Accepted 7 April 2014 Submitted
Volume:	Volume 15
Number:	Number 1
Article Number:	Article number 850
DOI:	10.1186/1471-2164-15-850
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access

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