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

Abstract

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.

• Authors: 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 Hoyng, Marius Ueffing, Marieke J H Coenen, Caroline C W Klaver, Anneke I den Hollander, EYE-RISK Consortium
• Journal: Ophthalmology (Ophthalmology) Vol. 128 Issue 11 Pg. 1604-1617 (11 2021) ISSN: 1549-4713 [Electronic] United States
• PMID: 32717343 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Eye Proteins
• DNA

Topics

• Aged
• Aged, 80 and over
• Case-Control Studies
• DNA (genetics)
• Eye Proteins (genetics, metabolism)
• Genetic Predisposition to Disease
• Genotype
• Humans
• Macular Degeneration (diagnosis, genetics, metabolism)
• Male
• Middle Aged
• Phenotype
• Polymorphism, Single Nucleotide
• Risk Factors