Corominas, Jordi, Colijn, Johanna M., Geerlings, Maartje J., Pauper, Marc ORCID: 0000-0001-6274-9891, Bakker, Bjorn, Amin, Najaf, Motta, Laura Lores, Kersten, Eveline, Garanto, Alejandro ORCID: 0000-0001-5721-1560, Verlouw, Joost A. M., van Rooij, Jeroen G. J., Kraaij, Robert, de Jong, Paulus T. V. M., Hofman, Albert, Vingerling, Johannes R., Schick, Tina, Fauser, Sascha, de Jong, Eiko K., van Duijn, Cornelia M., Hoyng, Carel B., Klaver, Caroline C. W. and den Hollander, Anneke I. (2018). Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane. Ophthalmology, 125 (9). S. 1433 - 1444. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1549-4713

Full text not available from this repository.

Abstract

Purpose: Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Design: Genome-wide case-control association study of WES data. Participants: One thousand one hundred twenty-five AMD patients and 1361 control participants. Methods: A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. Main Outcome Measures: Genetic variants associated with AMD. Results: We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07 x 10(-5)). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane. Conclusions: This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD. (C) 2018 by the American Academy of Ophthalmology.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Corominas, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colijn, Johanna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geerlings, Maartje J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauper, MarcUNSPECIFIEDorcid.org/0000-0001-6274-9891UNSPECIFIED
Bakker, BjornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amin, NajafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motta, Laura LoresUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kersten, EvelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garanto, AlejandroUNSPECIFIEDorcid.org/0000-0001-5721-1560UNSPECIFIED
Verlouw, Joost A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rooij, Jeroen G. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraaij, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Paulus T. V. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofman, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vingerling, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schick, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauser, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Eiko K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyng, Carel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klaver, Caroline C. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
den Hollander, Anneke I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-175433
DOI: 10.1016/j.ophtha.2018.03.040
Journal or Publication Title: Ophthalmology
Volume: 125
Number: 9
Page Range: S. 1433 - 1444
Date: 2018
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1549-4713
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COMPLEMENT FACTOR-H; HIGH-RISK; ASSOCIATION ANALYSIS; CRYSTAL-STRUCTURE; GENETIC-VARIANTS; CODING VARIANTS; GRADING SYSTEM; VIII COLLAGEN; DESIGN UPDATE; CFI GENEMultiple languages
OphthalmologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17543

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item