Uncovering the Genetic Architecture of Optic Nerve Integrity Estimates through Genome-wide Association Study Meta-analyses

Asma M. Aman; Santiago Díaz‐Torres; Samantha Sze‐Yee Lee; Sjoerd J. Driessen; Victor A. de Vries; Frank C. T. van der Heide; Antonia Kolovos; Joshua M. Schmidt; Henry N. Marshall; Lania Saleh; Alicia Schulze; Gabriëlla A.M. Blokland; Carroll A.B. Webers; Carla Kallen; Anke Wesselius; Ilja C.W. Arts; Freekje van Asten; Mathias Gorski; Martina E. Zimmermann; Klaus J. Stark; Iris M. Heid; Terri L. Young; Louis Robert Pasquale; Ayellet V. Segrè; Janey L. Wiggs; Anthony P. Khawaja; Alex William Hewitt; Alexander Karl-Georg Schuster; Tos T. J. M. Berendschot; Alberta A. H. J. Thiadens

doi:10.64898/2026.02.03.26345426

Genetic & Genomic MedicinemedRxivFeb 10, 2026

Preprint

Uncovering the Genetic Architecture of Optic Nerve Integrity Estimates through Genome-wide Association Study Meta-analyses

Asma M. Aman iD, Santiago Díaz‐Torres iD, Samantha Sze‐Yee Lee iD, Sjoerd J. Driessen, Victor A. de Vries iD, Frank C. T. van der Heide iD, Antonia Kolovos iD, Joshua M. Schmidt iD, Henry N. Marshall iD, Lania Saleh, Alicia Schulze iD, Gabriëlla A.M. Blokland iD, Carroll A.B. Webers iD, Carla Kallen iD, Anke Wesselius iD, Ilja C.W. Arts iD, Freekje van Asten iD, Mathias Gorski iD, Martina E. Zimmermann iD, Klaus J. Stark iD, Iris M. Heid iD, Terri L. Young iD, Louis Robert Pasquale iD, Ayellet V. Segrè iD, Janey L. Wiggs iD, , Puya Gharahkhani iD

Abstract

We conducted the first genome-wide association meta-analyses of global and sectoral peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruchs membrane opening-minimum rim width (BMO-MRW), the major optic nerve head structural and neurodegeneration biomarkers, including up to 25,942 and 12,080 participants, respectively, from the International Glaucoma Genetics Consortium. We identified 9 global pRNFL thickness and 9 global BMO-MRW loci, along with 28 and 19 loci for pRNFL and BMO-MRW sectors, respectively, comprising both shared and sector-specific loci. To identify intraocular pressure (IOP)-independent drug targets, global pRNFL thickness and BMO-MRW were conditioned on IOP. IOP-independent loci were then prioritised to identify candidate causal genes using transcriptome-wide association study and colocalization analysis. Several genes, such as NMNAT2 and TRIOBP, had robust associations with both phenotypes, with potential IOP-independent therapeutic translation for glaucoma. Overall, we identified novel loci for pRNFL thickness and BMO-MRW, highlighting potential drug-target genes acting independently from IOP, and elucidating genetic differences among pRNFL sectors.

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