Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease
Creators: name: Winkler, Thomas W.
name: Grassmann, Felix
name: Brandl, Caroline
name: Kiel, Christina
name: Günther, Felix
name: Strunz, Tobias
name: Weidner, Lorraine
name: Zimmermann, Martina E.
name: Korb, Christina A.
name: Poplawski, Alicia
name: Schuster, Alexander K.
name: Müller-Nurasyid, Martina
name: Peters, Annette
name: Rauscher, Franziska G.
name: Elze, Tobias
name: Horn, Katrin
name: Scholz, Markus
name: Cañadas-Garre, Marisa
name: McKnight, Amy Jayne
name: Quinn, Nicola
name: Hogg, Ruth E.
name: Küchenhoff, Helmut
name: Heid, Iris M.
name: Stark, Klaus J.
name: Weber, Bernhard H. F.
Publisher: name: Universität Regensburg
Year: 2020
Subjects: subject: 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
subject: 610 Medizin

description: 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 &gt; 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 &lt; 5 x 10(- 8)), (ii) one previously suggested locus with experiment-wise significance (P &lt; 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.