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

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, <i>LOXL1</i> and <i>CACNA1A</i>, 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 <i>LOXL1</i>, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at <i>LOXL1</i> (p.Phe407, odds ratio (OR) = 25, <i>P</i> = 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 (<i>P</i> < 5 × 10^-8). We identified association signals at 13q12 (<i>POMP</i>), 11q23.3 (<i>TMEM136</i>), 6p21 (<i>AGPAT1</i>), 3p24 (<i>RBMS3</i>) and 5q23 (near <i>SEMA6A</i>). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare <i>LOXL1</i> variants in disease biology.