GWAS-by-subtraction reveals an IOP-independent component of primary open angle glaucoma

Yu Huang (), Denis Plotnikov, Huan Wang, Danli Shi, Cong Li, Xueli Zhang, Xiayin Zhang, Shulin Tang, Xianwen Shang, Yijun Hu, Honghua Yu (), Hongyang Zhang (), Jeremy A. Guggenheim () and Mingguang He ()
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Yu Huang: Southern Medical University
Denis Plotnikov: Kazan State Medical University
Huan Wang: Ninewells Hospital and Medical School
Danli Shi: The Hong Kong Polytechnic University
Cong Li: Southern Medical University
Xueli Zhang: Southern Medical University
Xiayin Zhang: Southern Medical University
Shulin Tang: Southern Medical University
Xianwen Shang: Southern Medical University
Yijun Hu: Southern Medical University
Honghua Yu: Southern Medical University
Hongyang Zhang: Southern Medical University
Jeremy A. Guggenheim: Cardiff University
Mingguang He: Southern Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The etiology of primary open angle glaucoma is constituted by both intraocular pressure-dependent and intraocular pressure-independent mechanisms. However, GWASs of traits affecting primary open angle glaucoma through mechanisms independent of intraocular pressure remains limited. Here, we address this gap by subtracting the genetic effects of a GWAS for intraocular pressure from a GWAS for primary open angle glaucoma to reveal the genetic contribution to primary open angle glaucoma via intraocular pressure-independent mechanisms. Seventeen independent genome-wide significant SNPs were associated with the intraocular pressure-independent component of primary open angle glaucoma. Of these, 7 are located outside known normal tension glaucoma loci, 11 are located outside known intraocular pressure loci, and 2 are novel primary open angle glaucoma loci. The intraocular pressure-independent genetic component of primary open angle glaucoma is associated with glaucoma endophenotypes, while the intraocular pressure-dependent component is associated with blood pressure and vascular permeability. A genetic risk score for the intraocular pressure-independent component of primary open angle glaucoma is associated with 26 different retinal micro-vascular features, which contrasts with the genetic risk score for the intraocular pressure-dependent component. Increased understanding of these intraocular pressure-dependent and intraocular pressure-independent components provides insights into the pathogenesis of glaucoma.

Date: 2024
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DOI: 10.1038/s41467-024-53331-0

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