Targeted assessment of the chromosome 15 locus identifies a potential protective role for ISLR coding variants in exfoliation syndrome.

Abstract

Purpose : Common genetic polymorphisms within the chromosome 15 locus (where LOXL1 resides) show the strongest evidence of association to date with exfoliation syndrome. However, the signal for genetic association spans >1,000,000 base-pairs and >50 genes, making localization of the causative genes challenging. We hypothesize that apart from LOXL1, there could be other genes within the locus harboring strong association independent of the classical LOXL1 rs3825942 G>A variant.

Methods : We performed whole exome resequencing in 1,000 XFS cases and 1,000 controls from Japan. With this data, we created a reference panel for imputation of low frequency (defined as frequency <5%) coding changes into existing genome-wide association data for 3,000 XFS cases and 3,000 controls, also from Japan. All successfully imputed coding variants passing stringent quality checks were analyzed for association with XFS disease status using logistic regression.

Results : Apart from confirming strong association at LOXL1 rs3825942 and the previously reported protective rare variant (LOXL1 p. Y407F; P<5x10^-8 for both), we detected significant association at ISLR p. F142L. This amino acid substitution was found at 0.66% in XFS cases and 2% in controls (Odds Ratio = 0.32, P = 8.4x10^-11). This association with ISLR p. F142L remained significant even after adjusting for the classical LOXL1 p. G153D (rs3825942) (OR conditioned = 0.32, P = 4.9 x 10^-12) as well as locus-wide conditioning on LOXL1 p.G153D, LOXL1 p. Y407F, LOXL1 p. I516V, as well as LOXL1 rs2165241 )(OR conditioned = 0.36, P = 1.95x 10^-8)

Conclusions : Our results suggests that within the chromosome 15 locus, both LOXL1 and ISLR may contribute independent protective effects against XFS in Japanese. Our data provides further biological insights into the XFS disease process, and further improves the genetic resolution within the chromosome 15 locus.

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