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.

中文翻译：

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剥脱综合征的遗传关联研究确定了LOXL1和5个新的易感基因座的保护性稀有变异

剥脱综合征（XFS）是继发性青光眼最常见的已知危险因素，也是全世界失明的主要原因。以前已经将XXL与LOXL1和CACNA1A这两个基因的变体相关联。为了进一步阐明XFS的遗传基础，我们收集了XFS病例的全球样本以完善LOXL1的关联，该关联以前在整个人群中显示出不一致的结果，并确定了与XFS相关的新变体。我们在LOXL1处鉴定了罕见的保护性等位基因（p.Phe407，比值比（OR）= 25，P = 2.9×10 ^-14），通过对9个国家/地区的XFS案件和控件进行深入的重新排序。来自24个国家/地区的XFS病例和对照的全基因组关联研究（GWAS），然后在18个国家中进行复制，确定了七个全基因组重要位点（P <5×10 ^-8）。我们在13q12（POMP），11q23.3（TMEM136），6p21（AGPAT1），3p24（RBMS3）和5q23（靠近SEMA6A）处识别了关联信号。这些发现为XFS的病理学提供了生物学见解，并突出了天然存在的罕见LOXL1变体在疾病生物学中的潜在作用。