Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates. Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities

Policy Review Section

In this issue of the Policy Review Section, Keith Shaw of the Division of Government, University of Northumbria, Fred Robinson of the Department of Sociology and Social Policy, University of Durham and Margaret Curran of the Tyne and Wear Research and Intelligence Unit, examine the findings of a local authority survey of the membership of quangos in the North East. They argue that main areas of the public sector in the region are controlled by an unrepresentative group of individuals, often self-selecting with limited accountability to the local community. In the second article Alastair Adair, James Berry and Stanley McGreal of the School of the Built Environment, University of Ulster, examine the impact of public policy and administration on the housing market in Belfast and suggest that there is scope for a redirection of funds towards a programme of social and economic recovery through inner city regeneration and housing policies. Finally Alistair McCulloch, John Moxen and Seaton Baxter of the School of Public Administration, the Robert Gordon University, critically review the support given to the voluntary environmental sector in Scotland and argue that the Scottish Office should institute action research projects in the sector to facilitate its sustainable development strategy.

A late Middle Pleistocene temperate-periglacial-temperate sequence (oxygen isotope stages 7-5e) near Marsworth, Buckinghamshire, UK.

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Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation.

Funder: EMBLFunder: Alcon Young Investigator AwardFunder: UKRI Future Leaders FellowshipPhotoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease