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Background: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. Methods: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

Belfast provide core financial support for the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). Macular Society, College of Optometrists and Diabetes UK funded individual researchers. The sponsors and funding organisations had no role in the design or conduct of this research. No conflicting relationship exists for any author Running head: Vitreomacular interface features in NICOLA vitreomacular adhesion (VMA), vitreomacular interface (VMI), Vitreomacular traction (VMT), full thickness macular hole (FTMH), lamellar macular hole (LMH), age-related macular degeneration (AMD), epiretinal membrane (ERM), optical coherent tomography (OCT), the International Vitreomacular Traction Study (IVTS), spectral domain OCT (SD-OCT), Northern Ireland Cohort Study for the Longitudinal Study of Ageing (NICOLA), computer 32 assisted home interview (CAPI), self-completion questionnaires (SCQ), Northern Ireland 33 Clinical Research Facility (NICRF), Early Treatment Diabetic Retinopathy (ETDRS), Colour fundus photography (CFP), multicolour (MC), Network of Ophthalmic Reading Centres UK (NetWORC UK), psuedo macular hole (PMH), macular hole (MH), body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), Choroidal neovascularisation (CNV), geographic atrophy (GA), high-density lipoprotein cholesterol (HDL), confidence intervals (CI), odds ratios (OR).

33Background: Advanced age-related macular degeneration (AMD) is a leading cause of 34 blindness. While around half of the genetic contribution to advanced AMD has been 35 uncovered, little is known about the genetic architecture of the preceding early stages of the 36 diseases. 37Methods: To identify genetic factors for early AMD, we conducted a genome-wide association 38 meta-analysis with 14,034 early AMD cases and 91,214 controls from 11 sources of data 39 including data from the International AMD Genomics Consortium (IAMDGC) and the UK 40 Biobank (UKBB). We ascertained early AMD via color fundus photographs by manual grading 41 for 10 sources and by using an automated machine learning approach for >170,000 images 42 from UKBB. We searched for significant genetic loci in a genome-wide association screen 43 (P<5x10 -8 ) based on the meta-analysis of the 11 sources and via a candidate approach based 44 on 13 suggestive early AMD variants from Holliday et al 2013 (P<0.05/13, additional 3,432 45 early AMD cases and 11,235 controls). For the novel AMD regions, we conducted in-silico 46 follow-up analysis to prioritize causal genes and pathway analyses. 47 Results:We identified 11 loci for early AMD, 9 novel and 2 known for early AMD. Most of 48 these 11 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, APOE, 49 C2, C3, CETP, PVRL2, TNFRSF10A, VEGFA), except two that were completely novel to any 50 AMD. Among the 17 genes within the two novel loci, in-silico functional annotation suggested 51 CD46 and TYR as the most likely responsible genes. We found the presence or absence of 52 an early AMD effect to distinguish known pathways of advanced AMD genetics 53 (complement/lipid pathways or extracellular matrix metabolism, respectively). 54 Conclusions:Our data on early AMD genetics provides a resource comparable to the existing 55 data on advanced AMD genetics, which enables a joint view. Our large GWAS on early AMD 56 identified novel loci, highlighted shared and distinct genetics between early and advanced 57 AMD and provides insights into AMD etiology. The ability of early AMD effects to differentiate 58 the major pathways for advanced AMD underscores the biological relevance of a joint view on 59 early and advanced AMD genetics. 60 KEYWORDS 61Genome-wide association study (GWAS); Meta-analysis; Age-related macular degeneration 62 (AMD); Early AMD; CD46; TYR; International AMD Genomics Consortium (IAMDGC); UK 63 Biobank (UKBB); machine-learning; automated phenotyping 64 65 BACKGROUND 66Age-related macular degeneration (AMD) is the leading cause of irreversible central vision 67 impairment in industrialized countries. Advanced AMD presents as geographic atrophy (GA) 68 and/or neovascular (NV) complications (1). Typically, advanced AMD is preceded by clinically 69 asymptomatic and thus often unrecognized early disease stages. Early AMD is characterised 70 by differently sized yellowish accumulations of extracellular material between Bruch's 71 membrane and retinal pigment epithelium (RPE) or betwee...

). Evaluation of coronary artery disease as a risk factor for reticular pseudodrusen. British journal of ophthalmology, 1-7. DOI: 10.1136DOI: 10. /bjophthalmol-2017 Published in: British journal of ophthalmology Document Version: Peer reviewed version Queen's University Belfast -Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights © 2017 BMJ. This work is made available online in accordance with the publisher's policies. Please refer to any applicable terms of use of the publisher. General rightsCopyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights.