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Genome wide association meta analysis highlights light induced signaling as a driver for refractive error
journal contributionposted on 2023-05-21, 12:48 authored by Tedja, MS, Wojciechowski, R, Hysi, PG, Eriksson, N, Furlotte, NA, Verhoeven, VJM, Iglesias, AI, Meester-Smoor, MA, Tompson, SW, Fan, Q, Khawaja, AP, Cheng, CY, Hohn, R, Yamashiro, K, Wenocur, A, Grazal, C, Haller, T, Metspalu, A, Wedenoja, J, Jonas, JB, Wang, YX, Xie, J, Mitchell, P, Foster, PJ, Klein, BEK, Klein, R, Paterson, AD, Hosseini, SM, Shah, RL, Williams, C, Teo, YY, Tham, YC, Gupta, P, Zhao, W, Shi, Y, Saw, WY, Tai, ES, Sim, XL, Huffman, JE, Polasek, O, Hayward, C, Bencic, G, Rudan, I, Wilson, JF, Joshi, PK, Tsujikawa, A, Matsuda, F, Whisenhunt, KN, van der Spek, P, Haak, R, Meijers-Heijboer, H, van Leeuwen, EM, Iyengar, SK, Lass, JH, Hoffman, A, Rivadeneira, F, Uitterlinden, AG, V, JR, Lehtimaki, T, Raitakari, OT, Biino, G, Concas, MP, Haarman, AEG, Schwantes-An, TH, Igo JR, RP, Cuellar-Partida, G, Jhanji, V, Martin, NG, Craig, JE, Gharahkhani, P, Williams, KM, Nag, A, Rahi, JS, Cumberland, PM, Delcourt, C, Bellenguez, C, Ried, JS, Bergen, AA, Meitinger, T, Gieger, C, Wong, TY, Alexander HewittAlexander Hewitt, David MackeyDavid Mackey, Simpson, NP, Parssinen, O, Baird, PN, Vitart, Vi, Amin, N, van Duijn, CM, Bailey-Wilson, JE, Saw, SM, Stambolian, D, MacGregor, S, Guggenheim, JA, Tung, JY, Hammond, CJ, Klaver, CWC
Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
Publication titleNature Genetics
Department/SchoolMenzies Institute for Medical Research
Place of publicationNew York