Abstract
Both pterygium and pinguecula are ocular surface lesions associated with shared environmental risk factors, including ultraviolet (UV) radiation exposure. However, most pingueculae do not progress to pterygium, and while prior genetic studies suggest a genetic contribution to pterygium susceptibility, the difficulty of controlling for shared UV exposure has been a limiting factor. Here, we use array-based data and whole genome sequencing (WGS)-based data from the multiancestry All of Us Research Platform to perform a case-case genome-wide association study directly comparing individuals with pterygium to individuals with pinguecula to partially account for shared UV exposure. We aimed to identify loci associated with pterygium rather than pinguecula and to nominate candidate genes and regulatory mechanisms underlying this phenotypic divergence. Case-control study. A total of 1483 pterygium cases and 1768 pinguecula cases in the array-based analysis; 1368 pterygium cases and 1651 pinguecula cases in the WGS-based analysis. Genome-wide association testing was performed using PLINK2, statistical fine-mapping was performed using the Sum of Single Effects model, and expression quantitative trait locus (eQTL) associations were obtained from three databases. P values, odds ratios, and allelic frequencies of lead variants; size of credible sets; eQTL P values and effect sizes. One lead variant on chromosome 20 reached genome-wide significance in the WGS-based analysis and was near genome-wide significance in the array-based analysis. SIRPA and SIRPB1, which are involved in immune signaling pathways, are nearby genes with significant eQTL associations. A second genome-wide significant lead variant on chromosome 10 lies near XPNPEP1 and ADD3. One suggestive lead variant on chromosome 1 lies near TGFB2, which is known to contribute to pterygium pathogenesis via inducing fibroblast differentiation. A second suggestive lead variant on chromosome 2 lies near COL6A3, which was previously found to be downregulated in active pterygium. Pterygium and pinguecula share UV-associated exposure as a risk factor but exhibit partially distinct genetic susceptibility. Lead loci near SIRPA/SIRPB1, ADD3/XPNPEP1, TGFB2, and COL6A3 implicate immune regulation, epithelial remodeling, and fibrovascular and extracellular matrix pathways in pterygium rather than pinguecula, consistent with the clinical observation that most pingueculae do not progress to pterygium. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.