gms | German Medical Science

7th International Symposium on AMD: Age-related Macular Degeneration – Understanding Pathogenetic Mechanisms of Disease

20.09. - 21.09.2019, Baden-Baden

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Development of a genotyping assay for AMD: the EYE-RISK Consortium

Meeting Abstract

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  • Anita de Breuk - Nijmegen/NL; Donders Institute for Brain, Cognition and Behaviour, Nijmegen/NL
  • I.E. Acar - Nijmegen/NL; Donders Institute for Brain, Cognition and Behaviour, Nijmegen/NL
  • E. Kersten - Nijmegen/NL
  • M.M.V.A.P. Schijvenaars - Department of Human Genetics, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen/NL
  • M.A. Meester-Smoor - Rotterdam/NL; Department of Epidemiology, Erasmus Medical Center, Rotterdam/NL
  • C. Delcourt - Bordeaux/F
  • C.C.W. Klaver - Rotterdam/NL; Department of Epidemiology, Erasmus Medical Center, Rotterdam/NL
  • J. Monés - Barcelona/E
  • D. Pauleikhoff - Münster/D
  • R. Silva - Coimbra/P; Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra/P; Association for Innovation and Biomedical Research on Light and Image, Combria/P
  • S. Fauser - Köln/D
  • C.B. Hoyng - Nijmegen/NL
  • M.J.H. Coenen - Department of Human Genetics, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen/NL
  • A.I. den Hollander - Nijmegen/NL; Donders Institute for Brain, Cognition and Behaviour, Nijmegen/NL
  • Consortium EYE-RISK

7th International Symposium on AMD: Age-related Macular Degeneration - Understanding Pathogenetic Mechanisms of Disease. Baden-Baden, 20.-21.09.2019. Düsseldorf: German Medical Science GMS Publishing House; 2020. Doc19amd04

doi: 10.3205/19amd04, urn:nbn:de:0183-19amd041

Veröffentlicht: 5. Februar 2020

© 2020 de Breuk et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

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Background: 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.

Methods: We developed a genotyping assay based on single molecule molecular inversion probes and next generation sequencing covering 87 single nucleotide polymorphisms (SNPs), and the coding and flanking regions of 13 genes (ABCA4, ARMS2, C3, C9, CD46, CFB, CFH, CFI, CTNNA1, HTRA1, PRPH2, TIMP3, SLC16A8). We included DNA samples from five European cohorts. Quality control steps were applied to ensure high quality data. Rare variants were analyzed with gene-based burden tests. Logistic regression analysis was used to assess associations of rare damaging and loss of function variants with AMD.

Results: We genotyped 2,720 AMD patients and 1,299 controls. Seventy SNPs were successfully genotyped, while seventeen SNPs were discarded due to coverage problems, deviation from Hardy-Weinberg expectations (P<10-4), low genotype concordance (<95%) or a high proportion of missing genotypes per SNP (>10%). We observed a high concordance rate between our platform and other genotyping platforms (96.02%-99.96%). Allele frequencies of the majority of the SNPs were similar to previously reported data. We observed a significant burden of rare variants in the C3 gene (P=1.00 x 10-3) and the CFH gene (P=4.17 x 10-5) in AMD cases. The CFH and CFI genes carried more damaging and loss of function variants in cases compared to controls (CFH gene OR 2.1, P=0.09; CFI gene OR 8.4, P=0.04).

Conclusion: We developed a comprehensive AMD genotyping assay which successfully genotyped 70 SNPs and the coding regions of 13 genes. After further optimization the assay can be used for risk assessment of AMD development and AMD progression.