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Meta-Analysis
. 2010 Jun 10;6(6):e1000978.
doi: 10.1371/journal.pgen.1000978.

A genome-wide association study of optic disc parameters

Wishal D Ramdas  1 , Leonieke M E van Koolwijk, M Kamran Ikram, Nomdo M Jansonius, Paulus T V M de Jong, Arthur A B Bergen, Aaron Isaacs, Najaf Amin, Yurii S Aulchenko, Roger C W Wolfs, Albert Hofman, Fernando Rivadeneira, Ben A Oostra, Andre G Uitterlinden, Pirro Hysi, Christopher J Hammond, Hans G Lemij, Johannes R Vingerling, Caroline C W Klaver, Cornelia M van Duijn
Affiliations
Meta-Analysis

A genome-wide association study of optic disc parameters

Wishal D Ramdas et al. PLoS Genet. .

Abstract

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11)) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The −10log p-plots for the meta-analyzed RS-I/RS-II genome-wide association study.
Plot (A) of disc area and plot (B) of vertical cup-disc ratio. The upper line represents the genome-wide significance threshold: p = 5×10−8. The middle and bottom line represents the 10−5 and 10−4 respectively.
Figure 2
Figure 2. Regional plots of the three loci associated with optic disc area.
Plots (A–C) show the loci on on chromosome 1, 10, and 16, respectively.
Figure 3
Figure 3. Regional plots of the six loci associated with vertical cup-disc ratio.
Plots (A–F) show the loci on chromosome 9, 10, 11, 13, 14, and 22, respectively.
See this image and copyright information in PMC

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