Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with kno

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Analysing Comparative Advantage and Competitiveness: An Application to Australia's Textile and Clothing Industries

Australia's comparative advantage and competitiveness in textile and clothing (TAC) industries are analysed, using Balassa's revealed comparative advantage index and Vollrath's measures of competitiveness. The analysis based on Balassa's indices shows that Australia has a strong comparative disadvantage in textiles and clothing as aggregate commodity groups, but there is comparative advantage in sub–categories of ‘special textile products’, ‘floor coverage, tapestry etc’, and ‘fur clothing’. The analysis based on Vollrath's indices shows that Australia is not competitive in the world market with respect to aggregate commodity groups of textiles and clothing. Grubel–Loyd index of intra–industry trade was calculated for seven categories of textiles and two categories of clothing. The results show a rising trend in intra–industry trade in some of these categories of TAC products, implying that Australia increasingly exports and imports differentiated TAC products. Australian TAC industries may look to further promote exports of their products in the global market through increased product differentiation and improved quality and design

Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

10.1002/gepi.21886Genetic Epidemiology393207-21

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60–100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/ 2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells an

Erratum: Atomic layer deposition of a MoS2 film (Nanoscale (2014) 6 (10584-10588))

10.1039/c4nr90076fNanoscale6221400

Evaluating herbivore management outcomes and associated vegetation impacts

African savannas are characterised by temporal and spatial fluxes that are linked to fluxes in herbivore populations and vegetation structure and composition. We need to be concerned about these fluxes only when management actions cause the system to shift towards a less desired state. Large herbivores are a key attribute of African savannas and are important for tourism and biodiversity. Large protected areas such as the Kruger National Park (KNP) manage for high biodiversity as the desired state, whilst private protected areas, such as those adjacent to the KNP, generally manage for high income. Biodiversity, sustainability and economic indicators are thus required to flag thresholds of potential concern (TPCs) that may result in a particular set of objectives not being achieved. In large conservation areas such as the KNP, vegetation changes that result from herbivore impact, or lack thereof, affect biodiversity and TPCs are used to indicate unacceptable change leading to a possible loss of biodiversity; in private protected areas the loss of large herbivores is seen as an important indicator of economic loss. Therefore, the first-level indicators aim to evaluate the forage available to sustain grazers without deleteriously affecting the vegetation composition, structure and basal cover. Various approaches to monitoring for these indicators were considered and the importance of the selection of sites that are representative of the intensity of herbivore use is emphasised. The most crucial step in the adaptive management process is the feedback of information to inform management decisions and enable learning. Feedback loops tend to be more efficient where the organisation’s vision is focused on, for example, economic gain, than in larger protected areas, such as the KNP, where the vision to conserve biodiversity is broader and more complex. Conservation implications: In rangeland, optimising herbivore numbers to achieve the management objectives without causing unacceptable or irreversible change in the vegetation is challenging. This manuscript explores different avenues to evaluate herbivore impact and the outcomes of management approaches that may affect vegetation