Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease
BMC Genomics
Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease
David G Ashbrook 0
Robert W Williams
Lu Lu
Jason L Stein
Derrek P Hibar
Thomas E Nichols
Sarah E Medland
Paul M Thompson
Reinmar Hager 0
0 Computational and Evolutionary Biology, Faculty of Life Sciences, University of Manchester , Michael Smith Building, Oxford Road, Manchester M13 9PT , UK
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.
Comparative analysis; Hippocampus; MGST3; BXD
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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 Alzheimers. Such a reserve hypothesis of
neurological disease [6,7] has been proposed for Parkinsons
[8], Huntingtons [9] and Alzheimers [10] diseases. Lower
than average volume has been linked to a number of
disorders [11] including depression [12-16], Alzheimers 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
crossspecies approach to identify genes underlying a phenotype
of interest [21-25] (...truncated)