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

Huang, Yu, Plotnikov, Denis, Wang, Huan, Shi, Danli, Li, Cong, Zhang, Xueli, Zhang, Xiayin, Tang, Shulin, Shang, Xianwen, Hu, Yijun, Yu, Honghua, Zhang, Hongyang, Guggenheim, Jeremy A. ORCID: https://orcid.org/0000-0001-5164-340X and He, Mingguang 2024. GWAS-by-subtraction reveals an IOP-independent component of primary open angle glaucoma. Nature Communications 15 (1) , 8962. 10.1038/s41467-024-53331-0

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Optometry and Vision Sciences
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	18 October 2024
Date of Acceptance:	9 October 2024
Last Modified:	22 Oct 2024 09:16
URI:	https://orca.cardiff.ac.uk/id/eprint/173108

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