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 journalArticle

40 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

Fingerprint

Refractive Errors
Genome-Wide Association Study
Meta-Analysis
Light
Retina
Cell Physiological Phenomena
Vertebrate Photoreceptor Cells
Sclera
Retinal Pigment Epithelium
Myopia
Vascular Endothelium
Blindness
Synaptic Transmission
Computer Simulation
Extracellular Matrix
RNA
Genes

Cite this

CREAM ; 23andMe Research Team ; UK Biobank Eye and Vision Consortium. / Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. In: Nature Genetics. 2018 ; Vol. 50, No. 6. pp. 834-848.
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CREAM, 23andMe Research Team & UK Biobank Eye and Vision Consortium 2018, 'Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error' Nature Genetics, vol. 50, no. 6, pp. 834-848. https://doi.org/10.1038/s41588-018-0127-7

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.

In: Nature Genetics, Vol. 50, No. 6, 01.06.2018, p. 834-848.

Research output: Contribution to journalArticle

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T1 - Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

AU - CREAM

AU - 23andMe Research Team

AU - UK Biobank Eye and Vision Consortium

AU - Tedja, Milly S.

AU - Wojciechowski, Robert

AU - Hysi, Pirro G.

AU - Eriksson, Nicholas

AU - Furlotte, Nicholas A.

AU - Verhoeven, Virginie J.M.

AU - Iglesias, Adriana I.

AU - Meester-Smoor, Magda A.

AU - Tompson, Stuart W.

AU - Fan, Qiao

AU - Khawaja, Anthony P.

AU - Cheng, Ching Yu

AU - Höhn, René

AU - Yamashiro, Kenji

AU - Wenocur, Adam

AU - Grazal, Clare

AU - Haller, Toomas

AU - Metspalu, Andres

AU - Wedenoja, Juho

AU - Jonas, Jost B.

AU - Wang, Ya Xing

AU - Xie, Jing

AU - Mitchell, Paul

AU - Foster, Paul J.

AU - Klein, Barbara E.K.

AU - Klein, Ronald

AU - Paterson, Andrew D.

AU - Hosseini, S. Mohsen

AU - Shah, Rupal L.

AU - Williams, Cathy

AU - Teo, Yik Ying

AU - Tham, Yih Chung

AU - Gupta, Preeti

AU - Zhao, Wanting

AU - Shi, Yuan

AU - Saw, Woei Yuh

AU - Tai, E. Shyong

AU - Sim, Xue Ling

AU - Huffman, Jennifer E.

AU - Polašek, Ozren

AU - Hayward, Caroline

AU - Bencic, Goran

AU - Rudan, Igor

AU - Wilson, James F.

AU - Aung, Tin

AU - Veluchamy, Amutha B.

AU - Burdon, Kathryn P.

AU - Campbell, Harry

AU - Chen, Li Jia

AU - Chen, Peng

AU - Chen, Wei

AU - Chew, Emily

AU - Deangelis, Margaret M.

AU - Ding, Xiaohu

AU - Döring, Angela

AU - Evans, David M.

AU - Feng, Sheng

AU - Fleck, Brian

AU - Fogarty, Rhys D.

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AU - Guo, Xiaobo

AU - Haarman, Annet E.G.

AU - He, Mingguang

AU - Howe, Laura D.

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AU - Jhanji, Vishal

AU - Kähönen, Mika

AU - Kaprio, Jaakko

AU - Kemp, John P.

AU - Khaw, Kay Tee

AU - Khor, Chiea Chuen

AU - Krapohl, Eva

AU - Korobelnik, Jean François

AU - Lee, Kris

AU - Li, Shi Ming

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AU - Luben, Robert N.

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AU - McMahon, George

AU - Meguro, Akira

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AU - Panda-Jonas, Songhomitra

AU - Pang, Chi Pui

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AU - Plomin, Robert

AU - Rantanen, Taina

AU - Schache, Maria

AU - Seppälä, Ilkka

AU - Smith, George D.

AU - Pourcain, Beate St

AU - Tam, Pancy O.

AU - Tideman, J. Willem L.

AU - Timpson, Nicholas J.

AU - Vaccargiu, Simona

AU - Vatavuk, Zoran

AU - Wang, Jie Jin

AU - Wang, Ningli

AU - Wareham, Nick J.

AU - Wright, Alan F.

AU - Xu, Liang

AU - Yap, Maurice K.H.

AU - Yazar, Seyhan

AU - Yip, Shea Ping

AU - Yoshimura, Nagahisa

AU - Young, Alvin L.

AU - Zhao, Jing Hua

AU - Zhou, Xiangtian

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AU - Alipanahi, Babak

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AU - Bell, Robert K.

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AU - Elson, Sarah L.

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AU - Noblin, Elizabeth S.

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AU - Pitts, Steven J.

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AU - Sazonova, Olga V.

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AU - Barman, Sarah A.

AU - Barrett, Jenny H.

AU - Bishop, Paul N.

AU - Blows, Peter

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AU - Chan, Michelle

AU - Chua, Sharon

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AU - Joshi, Peter K.

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AU - Matsuda, Fumihiko

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AU - Vingerling, Johannes R.

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AU - Biino, Ginevra

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AU - Schwantes-An, Tae Hwi

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AU - Martin, Nicholas G.

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AU - Gharahkhani, Puya

AU - Williams, Katie M.

AU - Nag, Abhishek

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AU - Cumberland, Phillippa M.

AU - Delcourt, Cécile

AU - Bellenguez, Céline

AU - Ried, Janina S.

AU - Bergen, Arthur A.

AU - Meitinger, Thomas

AU - Gieger, Christian

AU - Wong, Tien Yin

AU - Hewitt, Alex W.

AU - Mackey, David A.

AU - Simpson, Claire L.

AU - Pfeiffer, Norbert

AU - Pärssinen, Olavi

AU - Baird, Paul N.

AU - Vitart, Veronique

AU - Amin, Najaf

AU - Van Duijn, Cornelia M.

AU - Bailey-Wilson, Joan E.

AU - Young, Terri L.

AU - Saw, Seang Mei

AU - Stambolian, Dwight

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41588-018-0127-7

DO - 10.1038/s41588-018-0127-7

M3 - Article

VL - 50

SP - 834

EP - 848

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -