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Milly S. Tedja, Robert Wojciechowski, Pirro G Hysi, Virginie JM Verhoeven, Christopher J Hammond, Caroline C W Klaver; Post-GWAS analysis on the molecular machinery in refractive error development. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1821. doi: https://doi.org/.
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Myopia is a complex genetic trait. A recent large GWAS meta-analysis on refractive error (RE) of CREAM and 23andMe (N=160,420) yielded 134 independent associated loci and found light processing to be a key player in myopiagenesis through pathway analyses. Despite all efforts, the molecular machinery behind key pathways remain largely unknown. Using post-GWAS analyses, we now investigate the molecular machinery and pathways behind the genetics of refractive error development.
We performed a post-GWAS gene-set and pathway analysis using Magma and FUMA tofind new pathways and additional evidence for light dependent pathways. Furthermore, we investigated chromatin structures and transcription factor binding sites in or near associated loci with FUMA.
Gene-set analysis showed significance in 15 gene sets, with eye development (PBonferroni = 2.84e-5) as highest association. Pathway analysis showed significance in > 50 pathways; highlights include the synaptic transmission (“neuronal system”, Padjusted = 1.98e-4; “transmission across chemical synapses”, Padjusted = 9.33e-4), circadian rhythm related genes (Padjusted = 2.81e-3 and matrisome pathway (Padjusted = 4.93e-3). 31 transcription factor binding sites were enriched (Padjusted range: 1.95e-8 – 0.049) and circos plots show complex intrachromosomal chromatin interactions and eQTL information for all index variants of the GWAS meta-analysis.
Our study underlines previously proposed light dependent pathways and indicates regulatory mechanisms interesting for future in-depth methylation analysis in myopiagenesis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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