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 A 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,

Research output: Contribution to journalArticleResearchpeer-review


PURPOSE: 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.

DESIGN: Case-control study.

PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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
Number of pages14
Issue number11
Early online dateNov 2021
Publication statusPublished - Nov 2021


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