Association of variants in FRAP1 and PDGFRA with corneal curvature in Asian populations from Singapore

Abstract

Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese and 3072 Malays, allowing us to identify two loci that were associated with CC variation: FRAP1 on chromosome 1p36.2 and PDGFRA on chromosome 4q12. These findings were subsequently replicated in a validation study involving an additional 2953 Asian Indians and a further collection of 1116 Chinese children. The effect sizes of the identified variants were consistent across all four cohorts, with seven single nucleotide polymorphisms (SNPs) in FRAP1 (lead SNP: rs17036350, meta P-value = 4.06 × 10(-13)) and six SNPs in PDGFRA (lead SNP: rs2114039, meta P-value = 1.33 × 10(-9)) attaining genome-wide significance in the SNP-based meta-analysis of the four studies. This is the first genome-wide survey of CC variation and we have identified two implicated loci in three genetically diverse Asian populations, suggesting the presence of common genetic etiology across multiple populations.

Evaluation of transethnic fine mapping with population-specific and cosmopolitan imputation reference panels in diverse Asian populations

“…Besides the cosmopolitan reference panel from 1000G project phase I, we possessed population-specific reference panels for Southeast Asian Malays 16 and South Asian Indians 17 that were generated from highcoverage whole-genome sequencing. The intention is to locate the potential protein-altering variants underpinning the association between 176 genetic loci sieved from the NIH GWAS catalog (http: //www.genome.gov/gwastudies) 18 with either eye-related traits such as corneal curvature (CC), central corneal thickness (CCT), corneal astigmatism (CA) and optic disk area (ODA) [19][20][21][22][23][24][25] or blood lipid measurements such as triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). [26][27][28][29][30] …”

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

“…This can be explained on the basis of the compensatory effects of other ocular biometric components, such as corneal curvature that influence the effect of an increased axial length through a flatter cornea 6 . Indeed, in genome-wide association studies (GWASs), some genes found to be associated with corneal curvature were also recently reported to be associated with axial length, but not with refractive error 7,13 .…”

The Genetic Background of Keratoconus: A Review on Keratoconus Genes

“…A recent study confirms the implication of PDGFRA in corneal curvature, detecting SNPs of PDGFRA and TRIM29 in Australians of Northern European ancestry [42]. Tripartite motif-containing protein 29 (TRIM29) with multiple zinc finger motifs and a leucine zipper motif, acts as a transcriptional regulatory factor and is involved in carcinogenesis and/or differentiation [42]. However, the same study did not reveal any effect of FRAP1 on corneal curvature [42].…”

“…Tripartite motif-containing protein 29 (TRIM29) with multiple zinc finger motifs and a leucine zipper motif, acts as a transcriptional regulatory factor and is involved in carcinogenesis and/or differentiation [42]. However, the same study did not reveal any effect of FRAP1 on corneal curvature [42].…”

“…The kinase activity of both proteins explains their effect on corneal epithelial cells and collagen fibrils and subsequently on corneal curvature [41]. A recent study confirms the implication of PDGFRA in corneal curvature, detecting SNPs of PDGFRA and TRIM29 in Australians of Northern European ancestry [42]. Tripartite motif-containing protein 29 (TRIM29) with multiple zinc finger motifs and a leucine zipper motif, acts as a transcriptional regulatory factor and is involved in carcinogenesis and/or differentiation [42].…”