Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.
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.
Tedja, MS; Wojciechowski, R; Hysi, PG; Eriksson, N; Furlotte, NA; Verhoeven, VJM; Iglesias, AI; Meester-Smoor, MA; Tompson, SW; Fan, Q; Khawaja, AP; Cheng, C-Y; Höhn, 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, W-Y; Tai, E-S; Sim, XL; Huffman, JE; Polašek, O; Hayward, C; Bencic, G; Rudan, I; Wilson, JF; CREAM Consortium, ; 23andMe Research Team, ; UK Biobank Eye and Vision Consortium, ; Joshi, PK; Tsujikawa, A; Matsuda, F; Whisenhunt, KN; Zeller, T; van der Spek, PJ; Haak, R; Meijers-Heijboer, H; van Leeuwen, EM; Iyengar, SK; Lass, JH; Hofman, A; Rivadeneira, F; Uitterlinden, AG; Vingerling, JR; Lehtimäki, T; Raitakari, OT; Biino, G; Concas, MP; Schwantes-An, T-H; Igo, RP; Cuellar-Partida, G; 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; Hewitt, AW; Mackey, DA; Simpson, CL; Pfeiffer, N; Pärssinen, O; Baird, PN; Vitart, V; Amin, N; van Duijn, CM; Bailey-Wilson, JE; Young, TL; Saw, S-M; Stambolian, D; MacGregor, S; Guggenheim, JA; Tung, JY; Hammond, CJ; Klaver, CCW
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