Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium

Anita de Breuk, Ilhan E. Acar, Eveline Kersten, Mascha M.V.A.P. Schijvenaars, Johanna M. Colijn, Lonneke Haer-Wigman, Bjorn Bakker, Sarah de Jong, Magda Meester-Smoor, Timo Verzijden, Tom O.A.R. Missotten, Jordi Monés, Marc Biarnés, Daniel Pauleikhoff, Hans W. Hense, Rufino Silva, Sandrina Nunes, Joana B. Melo, Sascha Fauser, Carel B. HoyngMarius Ueffing, Marieke J.H. Coenen, Caroline C.W. Klaver, Anneke I. den Hollander, Soufiane Ajana, Blanca Arango-Gonzalez, Franz Badura, Berta De la Cerda, Marc Biarnés, Anna Borrell, Johanna M. Colijn, Audrey Cougnard-Grégoire, Sascha Dammeier, Eiko K. de Jong, Cécile Delcourt, Anneke I. den Hollander, Sigrid Diether, Eszter Emri, Tanja Endermann, Lucia L. Ferraro, Míriam Garcia, Thomas J. Heesterbeek, Sabina Honisch, A. Ikram, Eveline Kersten, Ellen Kilger, Caroline C.W. Klaver, Hanno Langen, Imre Lengyel, Phil Luthert, Magda Meester-Smoor, Bénédicte M.J. Merle, Jordi Monés, Everson Nogoceke, Tunde Peto, Frances M. Pool, Eduardo Rodríguez, Marius Ueffing, Timo Verzijden, Johannes Vingerling, Markus Zumbansen

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To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD.

Case-control study.

Individuals (n = 4740) from 5 European cohorts.

We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis.

Main Outcome Measures
Genetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations.

We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy.

This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.
Original languageEnglish
Pages (from-to) 1604-1617
Issue number11
Early online date25 Jul 2020
Publication statusPublished - Nov 2021


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