Winkler, Thomas W. and Grassmann, Felix and Brandl, Caroline and Kiel, Christina and Guenther, Felix and Strunz, Tobias and Weidner, Lorraine and Zimmermann, Martina E. and Korb, Christina A. and Poplawski, Alicia and Schuster, Alexander K. and Mueller-Nurasyid, Martina and Peters, Annette and Rauscher, Franziska G. and Elze, Tobias and Horn, Katrin and Scholz, Markus and Canadas-Garre, Marisa and McKnight, Amy Jayne and Quinn, Nicola and Hogg, Ruth E. and Kuechenhoff, Helmut and Heid, Iris M. and Stark, Klaus J. and Weber, Bernhard H. F. (2020) Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease. BMC MEDICAL GENOMICS, 13 (1): 120. ISSN , 1755-8794
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MEMBRANE COFACTOR PROTEIN; RISK-FACTORS; GWAS; CD46; VARIANTS; RARE; CLASSIFICATION; EXPRESSION; EFFICIENT; RESOURCE; 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 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde Medicine > Lehrstuhl für Humangenetik Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2021 13:25 |
| Last Modified: | 15 Mar 2021 13:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43984 |
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