Journal
BMC MEDICAL GENOMICS
Volume 13, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12920-020-00760-7
Keywords
Genome-wide association study (GWAS); Meta-analysis; Age-related macular degeneration (AMD); Early AMD; CD46; TYR; International AMD genomics consortium (IAMDGC); UK biobank (UKBB); Machine-learning; Automated phenotyping
Categories
Funding
- German Federal Ministry of Education and Research (BMBF) [01ER1206, 01ER1507]
- University of Regensburg
- government of Rhineland-Palatinate [AZ 961-386261/733]
- Johannes Gutenberg-University of Mainz
- Boehringer Ingelheim
- PHILIPS Medical Systems
- Deutsche Ophthalmologische Gesellschaft
- Berufsverband der Augenarzte Deutschland e.V.
- NIH [R01 EY022310]
- DFG [HE 3690/5-1]
- Helmholtz Zentrum Munchen - German Research Center for Environmental Health
- German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Center of Health Sciences (MC-Health)
- LudwigMaximilians-Universitat
- Leipzig Research Centre for Civilization Diseases (LIFE)
- European Union
- European Regional Development Fund (ERDF)
- Free State of Saxony within the framework of the excellence initiative [713-241202, 14505/2470, 14575/2470]
- German Federal Ministry of Education and Research: i:DSem - Integrative data semantics in systems medicine [031 L0026]
- Lions Foundation
- GrimshawGudewicz Foundation
- Research to Prevent Blindness
- BrightFocus Foundation
- Alice Adler Fellowship
- NEI [R21EY030142, R21EY030631, R01EY030575, P30EYE003790]
- Atlantic Philanthropies
- Economic and Social Research Council
- UKCRC Centre of Excellence for Public Health Northern Ireland
- Centre for Ageing Research and Development in Ireland
- Office of the First Minister and Deputy First Minister
- Health and Social Care Research and Development Division of the Public Health Agency
- Wellcome Trust/Wolfson Foundation
- Queen's University Belfast
- Science Foundation Ireland
- Department for the Economy, Northern Ireland US [15/IA/3152]
- Economic and Social Research Council [ES/L008459/1]
- German Research Foundation (DFG) [HE-3690/5-1]
- National Institutes of Health (NIH) [R01 EY RES 511967]
- Academy of Sciences Leopoldina [LPDS 2018-06]
- Helmut-Ecker-Foundation [05/17]
- German Research Foundation [GR 5065/1-1]
- Projekt DEAL
- [HHSN268201200008I]
- ESRC [ES/L008459/1] Funding Source: UKRI
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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. Results Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 x 10(- 8)), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (nearARMS2/HTRA1, CFH,C2,C3,CETP,TNFRSF10A,VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggestedCD46andTYRas the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). Conclusions Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.
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