Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-Related Macular Degeneration Subtypes

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2×10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3×10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4×10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The machinist landscape:Land Art Generator Initiative (Competition)

THE MACHINIST LANDSCAPE: AN ENTROPIC GRID OF VARIANCE
‘By drawing a diagram, a ground plan of a house, a street plan to the location of a site, or a topographic map, one draws a “logical two dimensional picture”. A “logical picture” differs from a natural or realistic picture in that it rarely looks like the thing it stands for.’
A Provisional Theory of Non-Sites, Robert Smithson (1968)

Between design and ground there are variances, deviations and gaps. These exist as physical interstices between what is conceptualised and what is realised; and they reveal moments in the design process that resist the reconciliation of people and their environment (McHarg 1963). The Machinist Landscape interrogates the significance of these variances through the contrasting processes of coppice and photovoltaic energy. It builds on the potential of these gaps, and in doing so proposes that these spaces of variance can reveal the complexity of relationships between consumption and remediation, design and nature.
Fresh Kills Park, and in particular the draft master plan (2006), offers a framework to explore this artificial construct. Central to the Machinist Landscape is the analysis of the landfill gas collection system, planned on a notional 200ft grid. Variations are revealed between this diagrammatic grid measure and that which has been constructed on the site. These variances between the abstract and the real offer the Machinist Landscape a powerful space of enquiry. Are these gaps a result of unexpected conditions below ground, topographic nuances or natural phenomena? Does this space of difference, between what is planned and what is constructed, have the potential to redefine the dynamic processes and relations with the land?
The Machinist Landscape is structured through this space of variance with an ‘entropic grid’, the under-storey of which hosts a carefully managed system of short-rotation coppice (SRC). The coppice, a medieval practice related to energy, product, and space, operates on theoretical and programmatic levels. It is planted along a structure of linear bunds, stabilized through coppice pole retaining structures and enriched with nutrients from coppice produced bio-char. Above the coppice is built an upper-storey of photovoltaic (PV); its structures fabricated from the coppiced timber and the PV produced with graphene from coppice charcoal processes.