Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness

Zhikun Yang,Di Liu,Weihong Yu,Jingyun Yang

doi:10.1186/s12864-021-07860-3

Abstract

ObjectiveTo prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT).MethodsWe applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately.ResultsWe identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR = 4.15 × 10− 12), PTGDS (ILMN_1664464; PSMR = 6.88 × 10− 9) and C9orf142 (ILMN_1761138; PSMR = 8.09 × 10− 9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; PSMR = 5.89 × 10− 9), LCNL1 (ENSG00000214402.6; PSMR = 5.67 × 10− 8), and PTGDS (ENSG00000107317.7; PSMR = 1.92 × 10− 7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing.ConclusionWe identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

Highlights

The cornea is a highly collagenous and transparent tissue through which light reaches the interior structures of the eye
summary data-based Mendelian randomization (SMR) analysis in the European population In participants with European ancestry, we identified multiple genes showing pleiotropic association with central corneal thickness (CCT) after correction for multiple testing using FDR (Table 2)
It should be noted that the gene PTGDS was the top gene showing significant pleiotropic association in both SMR analyses

Summary

Introduction

The cornea is a highly collagenous and transparent tissue through which light reaches the interior structures of the eye. Previous studies highlighted the importance of central corneal thickness (CCT) in relation to several ocular and non-ocular conditions. Thinner CCT has been demonstrated as an important feature of keratoconus and a risk factor for primary open-angle glaucoma (POAG) in patients with ocular hypertension [2,3,4,5,6,7]. Keratoconus is the leading cause of corneal transplants worldwide, with an estimated prevalence of 0.14% [8], while POAG is the most common cause of irreversible blindness worldwide, accounting for approximately 70% of all the cases of glaucoma [9]. Previous genome-wide association studies (GWAS) identified a number of CCT-associated loci in Europeans and Asians, such as genetic loci in ZNF469, FOXO1, LRRK1 and IBTK [14,15,16,17,18,19,20]. Recent genetic studies revealed additional novel loci associated with CCT, some of which conferred relatively high risks of keratoconus and POAG, highlighting the potential involvement of CCT-associated genes underlying the pathogenesis of keratoconus and POAG [21, 22]

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Conclusion