Abstract
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. 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.
Highlights
The concordance rates of rare variants identified in the EYE-RISK smMIPs dataset compared with the whole exome sequencing dataset was more than 99% (Table S7)
In the EYE-RISK consortium, we developed a comprehensive genotype assay for age-related macular degeneration (AMD) and demonstrated the added value of extensive genetic testing for AMD
With regard to the role of rare genetic variants, we observed a higher occurrence of rare LoF variants or variants with a combined annotation-dependent depletion (CADD) score of 20 or more in the CFH, CFI, and C3 genes in late AMD patients compared with control individuals
Summary
It is important to evaluate genes that are involved in the pathogenesis of inherited macular dystrophies because the phenotype of some of these dystrophies can mimic AMD.20e22 The aim of this study was to develop a comprehensive AMD genotype assay to assess associations with AMD risk variants, to calculate an overall genetic risk score (GRS), and to differentiate between AMD and AMDmimicking dystrophies
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