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

BMC Genomics, Oct 2014

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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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 - 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)


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