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

CREAM Consortium, Milly S Tedja, Robert Wojciechowski, Pirro G Hysi, Nicholas Eriksson, Nicholas A Furlotte, Virginie J M Verhoeven, Adriana I Iglesias, Magda A Meester-Smoor, Stuart W Tompson, Qiao Fan, Anthony P Khawaja, Ching-Yu Cheng, René Höhn, Kenji Yamashiro, Adam Wenocur, Clare Grazal, Toomas Haller, Andres Metspalu, Juho WedenojaJost B Jonas, Ya Xing Wang, Jing Xie, Paul Mitchell, Paul J Foster, Barbara E K Klein, Ronald Klein, Andrew D Paterson, S Mohsen Hosseini, Rupal L Shah, Cathy Williams, Yik Ying Teo, Yih Chung Tham, Preeti Gupta, Wanting Zhao, Yuan Shi, Woei-Yuh Saw, E-Shyong Tai, Xue Ling Sim, Jennifer E Huffman, Ozren Polašek, Caroline Hayward, Goran Bencic, Igor Rudan, James F Wilson, Peter K Joshi, Akitaka Tsujikawa, Fumihiko Matsuda, Kristina N Whisenhunt, Tanja Zeller, Veronique Vitart

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)834-848
JournalNature Genetics
Volume50
Early online date28 May 2018
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Journal Article

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