Rare Variant TDT Association Study of Familial Myopia in Caucasian Families

Abstract

Purpose : Genome-wide association studies and linkage studies have identified loci influencing the risk of developing myopia but, few causal variants have been identified with the majority of them being common (minor allele frequency > 0.05). Therefore, this study aims to identify regions associated with rare variants that increase myopia risk using dense Exome Chip genotyping data from 75 myopic Caucasian families from the Penn Family Myopia Study.

Methods : 25 Myopic Caucasian parent-child trios (selected from multiplex families) were independently genotyped using the Illumina Human Exome v1.1 array plus. Myopia was defined based on mean spherical equivalent in Diopters (D): affected (≤-1D), unaffected (≥0 D) or unknown (<0D, >-1 D). After quality control, 27,121 SNPs were analyzed using a rare-variant transmission disequilibrium test (RV-TDT) to perform gene-based association tests with rare variants.

Results : RV-TDT analysis identified a suggestively associated locus on chromosome 2q31.1 for a non-synonymous coding SNP rs34564141 in the low density lipoprotein receptor-related protein 2 (LRP2) gene after correcting for multiple testing (P value = 2.65x10^-3). LRP2 has been implicated in a study of a rare form of severe myopia in patients who had a mutation in the LRP2 gene, encoding a receptor LRP2 in the retina. Additionally, greatly enlarged eyes have been observed in mice lacking this LRP2 gene.

Conclusions :
No detected associations met exome wide significance or nominal significance of an α level of 0.05 Bonferroni corrected for 11,362 genes. We are extending these analyses to include 350 individuals from additional myopic family cohorts, including Ashkenazi Jewish , African American, and Chinese families which we will present these results.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.