Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10−14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
At a glance
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- Supplementary Text and Figures (6,546 KB)
Supplementary Figures 1–23, Supplementary Tables 1–5, 8–13 and 15–17, and Supplementary Note.
- Supplementary Table 6 (14 KB)
Genome-wide significant (P < 5 × 10−8) SNPs emerging from the LOXL1 deep sequencing effort after fixed-effects meta-analysis is performed.
- Supplementary Table 7 (14 KB)
Details of all 63 amino acid substitutions (excluding the well-known rs3825942[G>A] for p.Gly153Asp and rs1048661[T>G] for p.Leu141Arg) that were detected from the deep resequencing of LOXL1 in 5,566 exfoliation syndrome cases and 6,279 controls from nine countries.
- Supplementary Table 14 (13 KB)
LD regions around each of the seven genome-wide significant loci for exfoliation syndrome.
- Supplementary Data 1 (24 KB)
Phased LOXL1 haplotypes from deep resequencing data.
- Supplementary Data 3 (24 KB)
INRICH pathway analysis.
- Supplementary Data 2 (35,681 KB)
Summary statistics for the genome-wide association study.