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Claire Simpson, Qing Li, Jeremy A Guggenheim, Joan E Bailey-Wilson, Cathy Williams, Robert Wojciechowski, CREAM Consortium; Case-Control Genome-Wide Association Study for Refractive Astigmatism: The CREAM Consortium. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4510. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To identify genetic variants that influence susceptibility to refractive astigmatism in the general population.
Meta-analyses of genome-wide association studies were carried out for (a) European adults aged at least 25 years old from 21 cohorts, total N=34,589; (b) Asian adults aged at least 25 years old from 7 cohorts, total N=9,295; (c) European youngsters aged <25 years old from 5 cohorts, total N=6,557; (d) the above three samples combined, total N=50,441. Participants were classified as refractive astigmatic cases if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. After genotyping on high-density SNP arrays and imputing using the HapMap-2 reference panel, genome-wide association analysis was carried out using a logistic regression model including terms for age and sex for each cohort separately. Meta analysis was conducted using a fixed effects model.
No marker reached genome-wide significance in any of the meta-analyses. For the European adults the top SNP was rs17795388 (P=7x10E-8) upstream of the neurexin-1 (NRXN1) gene. The top SNPs in the next 4 most strongly associated regions were rs12212674 (P=8x10E-07) within long intergenic non-coding RNA LINC00340, rs7829116 (P=1x10E-06) near COL14A1, rs2871434 (P=2x10E-06) near PCDH7 and rs12607243 (P=3x10E-06) near DSC3. The top SNP in European youngsters was rs6688613 (P=3x10E-06) near MAEL, and in Asian adults was rs7534824 (P=9x10E-07) near LOC101928334. In the meta analysis of all 33 cohorts, the NRXN1 and LINC00340 regions remained the most strongly associated, with rs10086929 (P=2x10E-6) downstream of the TOX gene next.
Two of the genomic regions associated with refractive astigmatism are associated with related ocular traits: SNPs at the TOX gene locus are associated with spherical equivalent refractive error, and SNPs within LINC00340 are associated with corneal curvature. This suggests potential genetic co-susceptibility for these traits (as seen with PDGFRA variants associated with corneal astigmatism, corneal curvature and axial length). Pcdhb9 is differentially expressed in an EGR-1 null mouse myopia model, suggesting potential involvement of the PCDH gene family in refractive development.
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