Family-based Genome-wide Association Study in South Indian Consanguineous Pedigrees Identifies an Association between WNT7B and Central Corneal Thickness

Abstract

Purpose: Central corneal thickness (CCT) is a highly heritable quantitative trait that is a risk factor of primary open angle glaucoma. The identification of genetic factors affecting CCT will provide insights into the mechanisms underlying the association between CCT and glaucoma. Although case-control population-based genome-wide association studies (GWAS) have identified several loci associated with CCT, family-based GWAS can have sufficient power to detect contributing variants with a smaller overall sample. The purpose of this study is to use consanguineous pedigrees from South India for family-based association studies for CCT.

Methods: CCT was measured for 240 members of 16 Indian consanguineous pedigrees using an ultrasonic pachymeter. CCT was measured in triplicate and the average value was used. Genotyping was performed using the Illumina HumanOmni2.5 SNP arrays. 1,223,314 SNPs were analyzed for association with CCT using the score test in MERLIN (v1.1.2). Sanger sequencing was applied for confirmation of the genotypes from SNP arrays.

Results: Using genome-wide genotype data a family-based association study was conducted for CCT. The best evidence for association was found in the WNT7B region. 9 of 57 SNPs within the WNT7B gene were associated with CCT (p < 0.05), including the top SNP rs9330813 (p = 1.71×10^-7) and a SNP rs62226057 located in the WNT7B promoter region (p = 0.00998). rs62226057 is evolutionarily conserved and is located within a DNase I hypersensitivity site suggesting that it may influence expression on WNT7B.

Conclusions: Our results suggest that SNPs in the WNT7B gene region are associated with CCT in this dataset. The associated SNPs are located in the 5’ regulatory region suggesting that the associated variants could influence gene expression. WNT7B is a member of the WNT signaling pathway previously shown to participate in the regulation of proliferation of human corneal limbal stem cells (LSCs)¹. Our results provide additional support for a role for WNT7B in corneal development and in particular the processes that contribute to central corneal thickness. Future studies investigating the effect of the associated variants on WNT7B gene expression would be of interest. ¹Nakatsu MN, et al. Wnt/β-catenin signaling regulates proliferation of human cornea epithelial stem/progenitor cells. IOVS. 2011; 52(7):4734-41.

Keywords: 539 genetics • 440 candidate gene analysis • 480 cornea: basic science