Refractive error is the most common eye disorder worldwide, and a prominent cause of blindness. Myopia affects over 30% of Western populations, and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses including 37,382 individuals from 27 studies of European ancestry, and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in subjects of European ancestry, of which 8 were shared with Asians. Combined analysis revealed 8 additional loci. The new loci include genes with functions in neurotransmission (GRIA4), ion channels (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2, BMP2), and eye development (SIX6, PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for subjects with the highest genetic load. Our results, accumulated across independent multi-ethnic studies, considerably advance understanding of mechanisms involved in refractive error and myopia.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (β = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (β = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (β = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (β = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (β = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (β = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

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