Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Nat Genet. 2017 Jul;49(7):993-1004. doi: 10.1038/ng.3875. Epub 2017 May 29.


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.

Publication types

  • Meta-Analysis

MeSH terms

  • Aged, 80 and over
  • Alleles
  • Amino Acid Oxidoreductases / genetics*
  • Amino Acid Oxidoreductases / physiology
  • Amino Acid Substitution
  • Asian People / genetics
  • Calcium Channels / genetics
  • Cell Adhesion
  • Exfoliation Syndrome / ethnology
  • Exfoliation Syndrome / genetics*
  • Extracellular Matrix / metabolism
  • Eye / metabolism
  • Female
  • Gene Expression Profiling
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Haplotypes
  • Humans
  • Male
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Mutation, Missense*
  • Point Mutation*
  • RNA, Messenger / biosynthesis
  • Spheroids, Cellular


  • CACNA1A protein, human
  • Calcium Channels
  • Molecular Chaperones
  • RNA, Messenger
  • proteasome maturation protein
  • Amino Acid Oxidoreductases
  • LOXL1 protein, human