Uncovering the Genetic Architecture of Optic Nerve Integrity Estimates through Genome-wide Association Study Meta-analyses
Aman, A. M.; Diaz-Torres, S.; Lee, S. S.-Y.; Driessen, S. J.; de Vries, V. A.; van der Heide, F. C. T.; Kolovos, A.; Schmidt, J. M.; Marshall, H. N.; Saleh, L.; Schulze, A.; Blokland, G. A.; Webers, C. A. B.; van der Kallen, C. J. H.; Wesselius, A.; Arts, I.; van Asten, F.; Gorski, M.; Zimmermann, M. E.; Stark, K. J.; Heid, I. M.; Young, T. L.; Pasquale, L. R.; Segre, A. V.; Wiggs, J. L.; Khawaja, A. P.; Hewitt, A. W.; Schuster, A. K.; Berendschot, T. T. J. M.; Thiadens, A. A. H. J.; van Garderen, K. A.; Klaver, C. C. W.; Hysi, P. G.; Hammond, C. J.; Brandl, C.; Craig, J. E.; Ramdas, W. D.; Ma
Show 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.
Matching journals
The top 12 journals account for 50% of the predicted probability mass.