A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness

Abstract

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders.

Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants

“…1, Supplementary Data 2), with the exception of strong but opposite-direction effects for the lead, low-frequency variant, rs112108520 at the ETS1 locus. Forty eight out of the 135 loci map CCT loci, identified in independent and smaller studies [6][7][8] , including thirteen which have been associated with keratoconus risk 5,6,8,22 (Supplementary Data 1). Using the International Genetics Glaucoma Consortium (IGGC) 6 CCT summary statistics for participants of European ancestry and linkage disequilibrium (LD) score regression method 23 , the genetic correlation between CRF and CCT is 70% (SE = 5%).…”

“…They comprised five coding variants (Supplementary Data 10 ), all missense with a high (>20) CADD score, a measure of the predicted deleterious consequence of the amino acid substitution 29 . All have been previously prioritized in relation to CCT 7 , 8 or keratoconus 11 , apart from rs77583146, p.Gly165Arg in WNT10A . This latter is 146 bp away from another low-frequency missense variant, rs121908120, reported for CCT and keratoconus risk 22 , identified here as an independent functional variant candidate.…”

“…Those were selfreported recent eye surgery (code 5181 in corresponding UK Biobank data-field), refractive laser surgery (code 5325), cataract surgery (code 5324), glaucoma high pressure surgery or laser treatment (codes 5326 and 5327), corneal graft surgery (code 5328), eye injury (code 5419); and the following electronic health records (data-fields 41202-41205):keratoconus (ICD10: H18.6; ICD9: 3716) or cornea disorders (ICD10: H18. [4][5][6][7][8][9].…”

“…orneal properties are clinically important 1,2 for: disease prognosis, electing refractive eye surgery, and evaluating intraocular pressure (IOP), a critical factor in glaucoma risk assessment. Genome-wide association studies (GWAS) for measurements acquired in heathy individuals-corneal thickness [3][4][5][6][7][8] , curvature 9,10 , resistance factor and hysteresis 11 , endothelial cells shape, and density 7 -showed potential to elucidate molecular events shaping these traits and associated disease risks. Statistical methods have emerged to narrow-down the genetic variants most likely to cause observed associations, with high throughput 12 .…”

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

“…Keratoconus can also be a comorbidity of other genetically determined conditions such as Down syndrome 13 . Several loci and variants for keratoconus have been identified through linkage studies and genomewide association studies (GWASs) for central corneal thickness (CCT) [14][15][16][17][18][19][20] . However, although CCT is highly heritable, it is a stable characteristic, in contrast to the acquired and progressive corneal thinning that is a feature of keratoconus.…”