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Meta-Analysis
. 2014 Sep 18;9(9):e107110.
doi: 10.1371/journal.pone.0107110. eCollection 2014.

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Claire L Simpson  1 , Robert Wojciechowski  2 , Konrad Oexle  3 , Federico Murgia  4 , Laura Portas  4 , Xiaohui Li  5 , Virginie J M Verhoeven  6 , Veronique Vitart  7 , Maria Schache  8 , S Mohsen Hosseini  9 , Pirro G Hysi  10 , Leslie J Raffel  11 , Mary Frances Cotch  12 , Emily Chew  12 , Barbara E K Klein  13 , Ronald Klein  13 , Tien Yin Wong  14 , Cornelia M van Duijn  15 , Paul Mitchell  16 , Seang Mei Saw  17 , Maurizio Fossarello  18 , Jie Jin Wang  19 ; DCCT/EDIC Research Group; Ozren Polašek  20 , Harry Campbell  21 , Igor Rudan  21 , Ben A Oostra  22 , André G Uitterlinden  23 , Albert Hofman  24 , Fernando Rivadeneira  23 , Najaf Amin  15 , Lennart C Karssen  15 , Johannes R Vingerling  6 , Angela Döring  25 , Thomas Bettecken  26 , Goran Bencic  27 , Christian Gieger  28 , H-Erich Wichmann  25 , James F Wilson  21 , Cristina Venturini  10 , Brian Fleck  29 , Phillippa M Cumberland  30 , Jugnoo S Rahi  31 , Chris J Hammond  10 , Caroline Hayward  7 , Alan F Wright  7 , Andrew D Paterson  9 , Paul N Baird  8 , Caroline C W Klaver  6 , Jerome I Rotter  5 , Mario Pirastu  4 , Thomas Meitinger  32 , Joan E Bailey-Wilson  1 , Dwight Stambolian  33
Collaborators, Affiliations
Meta-Analysis

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Claire L Simpson et al. PLoS One. .

Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Q-Q and Manhattan Plots for the myopia analysis of all cohorts.
a) Q-Q plot for association between all SNPs analyzed and myopia in the meta-analysis. Each dot represents an observed statistic (defined as -log10 P) versus the corresponding expected statistic. The red line corresponds to the null distribution. b) Manhattan plot for association between all SNPs analyzed and myopia in the meta-analysis. Each dot represents an observed statistic (defined as -log10 P). The darker gray line corresponds to the genome-wide significance threshold and the lighter gray line represents the suggestive threshold.
Figure 2
Figure 2. Q-Q and Manhattan Plots for the hyperopia analysis of all cohorts.
a) Q-Q plot for association between all SNPs analyzed and hyperopia in the meta-analysis. Each dot represents an observed statistic (defined as -log10 P) versus the corresponding expected statistic. The red line corresponds to the null distribution. b) Manhattan plot for association between all SNPs analyzed and hyperopia in the meta-analysis. Each dot represents an observed statistic (defined as -log10 P). The darker gray line corresponds to the genome-wide significance threshold and the lighter gray line represents the suggestive threshold.
Figure 3
Figure 3. Q-Q and Manhattan Plots for the myopia analysis excluding the ERF cohort a) Q–Q plot for association between all SNPs analyzed and myopia in the meta-analysis excluding the ERF cohort.
Each dot represents an observed statistic (defined as -log10 P) versus the corresponding expected statistic. The red line corresponds to the null distribution. b) Manhattan plot for association between all SNPs analyzed and myopia in the meta-analysis excluding the ERF cohort. Each dot represents an observed statistic (defined as -log10 P). The darker gray line corresponds to the genome-wide significance threshold and the lighter gray line represents the suggestive threshold.
Figure 4
Figure 4. Q-Q and Manhattan Plots for the hyperopia analysis excluding the ERF cohort a) Q-Q plot for association between all SNPs analyzed and hyperopia in the meta-analysis excluding the ERF cohort.
Each dot represents an observed statistic (defined as -log10 P) versus the corresponding expected statistic. The red line corresponds to the null distribution. b) Manhattan plot for association between all SNPs analyzed and hyperopia in the meta-analysis excluding the ERF cohort. Each dot represents an observed statistic (defined as -log10 P). The darker gray line corresponds to the genome-wide significance threshold and the lighter gray line represents the suggestive threshold.
See this image and copyright information in PMC

References

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