Heritability and Genetic Factors of Astigmatism and Corneal Curvature: A Systematic Review and Meta-analysis

Abstract

PurposeTo systematically review and meta-analyze all reported heritability studies of refractive astigmatism (RA), corneal astigmatism (CA) and corneal curvature (CC), and evaluate the existing genetic associations of RA, CA and CC. DesignSystematic review and meta-analysis (PROSPERO ID: CRD42023447370). MethodsStudies that reported the heritability and genetic associations of RA, CA and/or CC were identified from PubMed, Web of Science and EMBASE (from inception to October 1, 2023). Newcastle-Ottawa Scale criteria was used to assess the risk of bias. Meta-analyses of heritability were conducted using random-effects model for mean difference. All current genetic associations were catalogued according to level of statistical significance. ResultsPooled heritabilities were moderate for RA (h2 = 0.46, 95% CI: 0.27 – 0.65), CA (h2 = 0.48, 95% CI: 0.38 – 0.58) and CC (h2 = 0.64, 95% CI: 0.53 – 0.76). Subgroup analyses revealed significant differences between analysis methods (CA: P < 0.01; CC: P = 0.03) and populations (CA: P < 0.01; CC: P < 0.01) in both CA and CC, and between age groups in CA (P < 0.01). Totally 50 single-nucleotide polymorphisms (SNPs) in 10 genes have been reported with overlapping associations with RA, CA and/or CC, with BMP3, FMNL2, HERC2, PROX1-AS1 and ZC3H11B associated with RA and CA, FBN1, NHSL1 and PDGFRA with CA and CC, TRAF3IP1 with RA and CC; and CASC15 with RA, CA and CC. ConclusionsThis study confirms moderate heritabilities of RA, CA and CC. Through evaluating overlapping SNPs or genes between these three phenotypes, we prioritized 50 SNPs in 10 genes as candidate variants for further validation. These findings highlight the complex genetic architecture of astigmatism and indicate shared and distinct genetic markers for different astigmatism-related corneal parameters. Future studies in different populations and functional studies evaluating the roles of the involved genes in astigmatism are warranted.