Family-based Genome-wide Association Study in South Indian Consanguineous Pedigrees Identifies an Association between LPHN3 and Vertical Cup-disc Ratio

Abstract

Purpose : Vertical cup-disc ratio (VCDR) is a highly heritable quantitative trait that is a critical clinical measurement for glaucoma diagnosis. Family-based genome-wide association studies (GWAS) can be an efficient and powerful approach to detect genetic variants associated with complex traits. In addition, investigations using geographic and culturally isolated populations can provide unique opportunities to study complex diseases on a relatively homogeneous genetic and environmental background. Previously we measured 45 ocular quantitative traits in 16 consanguineous pedigrees from South India and completed GWAS and linkage analyses for each trait. The purpose of this study is to conduct a family-based association study for VCDR in this South Indian population.

Methods : 240 individuals of 16 consanguineous pedigrees from South India were measured for VCDR by Heidelberg Retina Tomograph. VCDR was measured in triplicate and the average value was used after adjusting for age and sex and normalizing by inverse-normal transformation of ranks prior to association tests. Genotyping was performed using the Illumina HumanOmni2.5-8 platform. 1,223,314 SNPs were screened for association with VCDR using the score test and suggestive associations were accurately evaluated using the likelihood-ratio test in MERLIN.

Results : The best evidence for association was found on chromosome 4 in a genomic region that includes LPHN3, with two SNPs reaching genome-wide significance: rs13435710 [A] (p = 2.6×10^-8, β = -1.110, s.e.= 0.211) and rs6849633 [C] (p = 4.1×10^-8, β = -0.709, s.e.= 0.138). While these SNPs were not significantly associated with VCDR in an independent Latino case-control cohort (n = 4,537, p = 0.73 and 0.25 respectively), the lead SNP rs13435710 (β = -0.016, s.e. = 0.046) did show the same direction of effect, providing some support for replication.

Conclusions : LPHN3 is associated with VCDR in this Indian dataset. LPHN3 is a transmembrane receptor with an extracellular olfactomedin domain, and plays a role in cell-cell adhesion and neuron guidance. Human proteome studies indicate that the gene is highly expressed in retinal tissue, and expression of LPHN3 is increased in a transgenic mouse with elevated myocilin.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.