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

  • 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 Wedenoja
  • Jost 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
  • Peter J van der Spek
  • Roxanna Haak
  • Hanne Meijers-Heijboer
  • Elisabeth M van Leeuwen
  • Sudha K Iyengar
  • Jonathan H Lass
  • Albert Hofman
  • Fernando Rivadeneira
  • André G Uitterlinden
  • Johannes R Vingerling
  • Terho Lehtimäki
  • Olli T Raitakari
  • Ginevra Biino
  • Maria Pina Concas
  • Tae-Hwi Schwantes-An
  • Robert P Igo
  • Gabriel Cuellar-Partida
  • Nicholas G Martin
  • Jamie E Craig
  • Puya Gharahkhani
  • Katie M Williams
  • Abhishek Nag
  • Jugnoo S Rahi
  • Phillippa M Cumberland
  • Cécile Delcourt
  • Céline Bellenguez
  • Janina S Ried
  • Arthur A Bergen
  • Thomas Meitinger
  • Christian Gieger
  • Tien Yin Wong
  • Alex W Hewitt
  • David A Mackey
  • Claire L Simpson
  • Norbert Pfeiffer
  • Olavi Pärssinen
  • Paul N Baird
  • Veronique Vitart
  • Najaf Amin
  • Cornelia M van Duijn
  • Joan E Bailey-Wilson
  • Terri L Young
  • Seang-Mei Saw
  • Dwight Stambolian
  • Stuart MacGregor
  • Jeremy A Guggenheim
  • Joyce Y Tung
  • Christopher J Hammond
  • Caroline C W Klaver
  • CREAM Consortium

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.

Bibliographical metadata

Original languageEnglish
ISSN1061-4036
DOIs
Publication statusPublished - 06.2018
PubMed 29808027