Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Abstract

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.

Metadata

Item Type:	Article
Authors/Creators:	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 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 Jr, 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
Copyright, Publisher and Additional Information:	© 2018 Nature America Inc., part of Springer Nature. This is an author produced version of a paper published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: June 2018 Published (online): 28 May 2018 Accepted: 26 March 2018
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	22 Jan 2019 14:33
Last Modified:	22 Jan 2019 14:33
Status:	Published
Publisher:	Springer Nature
Identification Number:	10.1038/s41588-018-0127-7
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:141402

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Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

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