PubMed ID: 41674619
Author(s): Aman AM, Diaz-Torres S, Lee SS, Driessen SJ, de Vries VA, van der Heide FCT, Kolovos A, Schmidt JM, Marshall HN, Saleh L, Schulze A, Blokland GA, Webers CAB, van der Kallen CJH, Wesselius A, Arts I, van Asten F, Gorski M, Zimmermann ME, Stark KJ, Heid IM, Young TL, Pasquale LR, Segre AV, Wiggs JL, Khawaja AP, Hewitt AW, Schuster AK, Berendschot TTJM, Thiadens AAHJ, van Garderen KA, Klaver CCW, Hysi PG, Hammond CJ, Brandl C, Craig JE, Ramdas WD, MacGregor S, Mackey DA, Gharahkhani P. Uncovering the Genetic Architecture of Optic Nerve Integrity Estimates through Genome-wide Association Study Meta-analyses. medRxiv [Preprint]. 2026 Feb 6:2026.02.03.26345426. doi: 10.64898/2026.02.03.26345426. PMID 41674619
Journal: Med Rxiv : The Preprint Server For Health Sciences, Feb 2026
We conducted the first genome-wide association meta-analyses of global and sectoral peripapillary retinal nerve fibre layer (pRNFL) thickness and Bruch’s 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.