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

CREAM, 23andMe Research Team, UK Biobank Eye and Vision Consortium

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

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
Number of pages15
JournalNature Genetics
Volume50
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018
Externally publishedYes

Bibliographical note

Funding Information:
We gratefully thank all study participants, their relatives and the staff at the recruitment centers for their invaluable contributions. We thank all contributors to the CREAM Consortium, 23andMe and UKEV for their generosity in sharing data and help in the production of this publication. Funding for this particular GWAS mega-analysis was provided by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant 648268), the Netherlands Organisation for Scientific Research (NWO, grant 91815655) and the National Eye Institute (grant R01EY020483). Funding agencies that facilitated the execution of the individual studies are acknowledged in the Supplementary Note.

Funding Information:
We gratefully thank all study participants, their relatives and the staff at the recruitment centers for their invaluable contributions. We thank all contributors to the CREAM Consortium, 23andMe and UKEV for their generosity in sharing data and help in the production of this publication. Funding for this particular GWAS mega-analysis was provided by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant 648268), the Netherlands Organisation for Scientific Research (NWO, grant 91815655) and the National Eye Institute (grant R01EY020483). Funding agencies that facilitated the execution of the individual studies are acknowledged in the Supplementary Note.

Publisher Copyright:
© 2018 The Author(s).

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