July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Development of a Genotyping Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium
Author Affiliations & Notes
  • Anita de Breuk
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • Ilhan Erkin Acar
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • Magda Meester
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Mascha MVAP Schijvenaars
    Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Netherlands
  • Eveline Kersten
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • Jordi Mones
    Institut de la Màcula, Barcelona, Spain
  • Daniel Pauleikhoff
    Ophthalmology Department, St. Franziskus Hospital, Münster, Germany
  • Rufino Silva
    Department of Ophthalmology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal
  • Sascha Fauser
    Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
  • Carel C B Hoyng
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • Cecile DelCourt
    Inserm UMR1219-Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France
  • Caroline C W Klaver
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
  • Marieke JH Coenen
    Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Netherlands
  • Anneke I Den Hollander
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Anita de Breuk, None; Ilhan Erkin Acar, None; Magda Meester, None; Mascha Schijvenaars, None; Eveline Kersten, None; Jordi Mones, None; Daniel Pauleikhoff, Bayer (C), Heidelberg Engineering (C), Novartis (C); Rufino Silva, Alcon (C), Alimera (C), Allergan (C), Bayer (C), THEA (C); Sascha Fauser, Roche (E); Carel Hoyng, None; Cecile DelCourt, Allergan (C), Bausch+Lomb (C), Laboratoires Théa (C), Novartis (C), Roche (C); Caroline Klaver, None; Marieke Coenen, None; Anneke Den Hollander, Gyroscope (C), Ionis Farmaceuticals (C)
  • Footnotes
    Support  Netherlands Organisation for Scientific Research (016.Vici.170.024 to AIdH) and European Union's Horizon 2020 research and innovation programme (grant agreement No. 634479 EYE-RISK)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2955. doi:https://doi.org/
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    • Get Citation

      Anita de Breuk, Ilhan Erkin Acar, Magda Meester, Mascha MVAP Schijvenaars, Eveline Kersten, Jordi Mones, Daniel Pauleikhoff, Rufino Silva, Sascha Fauser, Carel C B Hoyng, Cecile DelCourt, Caroline C W Klaver, Marieke JH Coenen, Anneke I Den Hollander; Development of a Genotyping Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2955. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Current genetic tests for age-related macular degeneration (AMD) are limited to a low number of genetic variants and vary widely in their risk assessment capacity. We aimed to develop an AMD genotyping assay that covers all currently known genetic variants and that can detect novel rare coding variants in AMD-related and AMD-mimicking genes, in order to establish genetic risk scores for AMD, to assess associations of genetic variants with AMD, and to establish a validated genotyping assay for AMD.

Methods : We developed a genotyping assay based on single molecule molecular inversion probes (smMIPs) and next generation sequencing (NGS) covering 87 single nucleotide polymorphisms (SNPs), and the coding and flanking regions of 10 AMD-related genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, SLC16A8) and 3 AMD-mimicking genes (ABCA4, CTNNA1, PRPH2). 4,718 DNA samples from five different European cohorts (EUGENDA, CES, MARS, CORRBI, GAIN) were available for genotyping. Reads were mapped using BWA and variant calling was performed by GATK and SAMtools. Quality control steps were applied to ensure high quality genotyping data.

Results : In total we genotyped 4,718 samples of 2,428 AMD patients and 1,297 control individuals. Seventy SNPs were successfully genotyped, while seventeen SNPs were discarded due to coverage or mapping problems, deviation from Hardy-Weinberg expectations (P < 10-4), low genotype concordance with other genotyping platforms (< 95%) or a high proportion of missing genotypes per SNP (>10%). For the 70 successfully genotyped SNPs we observed a high concordance rate between our platform and other genotyping platforms (96.02% - 99.96%). Allele frequencies of the SNPs and odds ratios for association with AMD were similar to previously reported data. Sequencing of the coding and flanking regions of 10 AMD-related and 3 AMD-mimicking genes identified 2,830 different rare coding or splice site variants, which will be further analyzed for their involvement in AMD by single variant association tests, gene burden tests, and genotype-phenotype correlations.

Conclusions : We developed a comprehensive AMD genotyping assay which successfully genotyped 70 SNPs and the coding regions of 13 AMD-related and AMD-mimicking genes. After further optimization this assay will be part of an AMD prediction website for risk assessment of AMD development and AMD progression.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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