Journal Article

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

Hewitt, Alex W., Teo, Yik Ying, Vingerling, Johannes R., Nag, Abhishek, Bergen, Arthur A., Hammond, Christopher J., Amin, Najaf, Haak, Roxanna, Williams, Cathy, Iglesias, Adriana I., Saw, Woei-Yuh, Cuellar-Partida, Gabriel, Rudan, Igor, Cumberland, Phillippa M., Klein, Ronald, Meester-Smoor, Magda A., Klaver, Caroline C. W., Polašek, Ozren, Concas, Maria Pina, Pärssinen, Olavi, Huffman, Jennifer E., Martin, Nicholas G., Hayward, Caroline, van Leeuwen, Elisabeth M., Hysi, Pirro G., Wedenoja, Juho, Zeller, Tanja, Joshi, Peter K., Gieger, Christian, Bailey-Wilson, Joan E., Verhoeven, Virginie J. M., Young, Terri L., Igo, Robert P., Bellenguez, Céline, Shi, Yuan, Meijers-Heijboer, Hanne, Uitterlinden, André G., Tedja, Milly S., Shah, Rupal L., Baird, Paul N., Yamashiro, Kenji, Saw, Seang-Mei, Fan, Qiao, Tung, Joyce Y., Sim, Xue Ling, Wong, Tien Yin, Gupta, Preeti, Biino, Ginevra, Jonas, Jost B., Whisenhunt, Kristina N., Bencic, Goran, Matsuda, Fumihiko, Williams, Katie M., Guggenheim, Jeremy A., Wenocur, Adam, Schwantes-An, Tae-Hwi, Ried, Janina S., van Duijn, Cornelia M., Mitchell, Paul, Rahi, Jugnoo S., K

2018

Overview

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. Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 631/208/205/2138 / 692/308 / 692/699 / Adult / Agriculture / Angiogenesis / Animal Genetics and Genomics / Asian People - genetics / Asians / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Blindness / Blindness - genetics / Blindness - metabolism / Cancer Research / Consortia / Endothelium / Epithelium / Europeans / Extracellular matrix / Eye / Eye diseases / Eye disorders / Female / Gene Expression Regulation / Gene Function / Gene regulation / Genes / Genetic aspects / Genetic Predisposition to Disease / Genome-Wide Association Study - methods / Genomes / Genomics / Human Genetics / Humans / Life Sciences / Male / Medical schools / Meta-analysis / Morphology / Myopia / Myopia - genetics / Neurotransmission / Novels / Polymorphism, Single Nucleotide / Post-transcription / Quality control / Refractive errors / Refractive Errors - genetics / Refractive Errors - metabolism / Retina / Retina - metabolism / Retinal cells / Retinal pigment epithelium / Retinal Pigment Epithelium - metabolism / Risk factors / Santé publique et épidémiologie / Signal Transduction / Signaling / Studies / Transcription (Genetics) / White People - genetics