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; The CREAM Consortium; 23andMe Research Team; UK Biobank Eye and Vision Consortium; 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

doi:10.1038/s41588-018-0127-7

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

Research output: Contribution to journal › Article › Research › peer-review

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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 language	English
Pages (from-to)	834-848
Number of pages	15
Journal	Nature Genetics
Volume	50
Issue number	6
DOIs	https://doi.org/10.1038/s41588-018-0127-7
Publication status	Published - 1 Jun 2018
Externally published	Yes

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Tedja, M. S., Wojciechowski, R., Hysi, P. G., Eriksson, N., Furlotte, N. A., Verhoeven, V. J. M., Iglesias, A. I., Meester-Smoor, M. A., Tompson, S. W., Fan, Q., Khawaja, A. P., Cheng, C. Y., Höhn, R., Yamashiro, K., Wenocur, A., Grazal, C., Haller, T., Metspalu, A., Wedenoja, J., ... Stambolian, D. (2018). Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nature Genetics, 50(6), 834-848. https://doi.org/10.1038/s41588-018-0127-7

@article{0738a4e4d261437886199c62e43ca135,

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

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.",

author = "Tedja, {Milly S.} and Robert Wojciechowski and Hysi, {Pirro G.} and Nicholas Eriksson and Furlotte, {Nicholas A.} and Verhoeven, {Virginie J.M.} and Iglesias, {Adriana I.} and Meester-Smoor, {Magda A.} and Tompson, {Stuart W.} and Qiao Fan and Khawaja, {Anthony P.} and Cheng, {Ching Yu} and Ren{\'e} H{\"o}hn and Kenji Yamashiro and Adam Wenocur and Clare Grazal and Toomas Haller and Andres Metspalu and Juho Wedenoja and Jonas, {Jost B.} and Wang, {Ya Xing} and Jing Xie and Paul Mitchell and Foster, {Paul J.} and Klein, {Barbara E.K.} and Ronald Klein and Paterson, {Andrew D.} and Hosseini, {S. Mohsen} and Shah, {Rupal L.} and Cathy Williams and Teo, {Yik Ying} and Tham, {Yih Chung} and Preeti Gupta and Wanting Zhao and Yuan Shi and Saw, {Woei Yuh} and Tai, {E. Shyong} and Sim, {Xue Ling} and Huffman, {Jennifer E.} and Ozren Pola{\v s}ek and Caroline Hayward and Goran Bencic and Igor Rudan and Wilson, {James F.} and {The CREAM Consortium} and {23andMe Research Team} and {UK Biobank Eye and Vision Consortium} and Joshi, {Peter K.} and Akitaka Tsujikawa and Fumihiko Matsuda and Whisenhunt, {Kristina N.} and Tanja Zeller and {Van Der Spek}, {Peter J.} and Roxanna Haak and Hanne Meijers-Heijboer and {Van Leeuwen}, {Elisabeth M.} and Iyengar, {Sudha K.} and Lass, {Jonathan H.} and Albert Hofman and Fernando Rivadeneira and Uitterlinden, {Andr{\'e} G.} and Vingerling, {Johannes R.} and Terho Lehtim{\"a}ki and Raitakari, {Olli T.} and Ginevra Biino and Concas, {Maria Pina} and Schwantes-An, {Tae Hwi} and Igo, {Robert P.} and Gabriel Cuellar-Partida and Martin, {Nicholas G.} and Craig, {Jamie E.} and Puya Gharahkhani and Williams, {Katie M.} and Abhishek Nag and Rahi, {Jugnoo S.} and Cumberland, {Phillippa M.} and C{\'e}cile Delcourt and C{\'e}line Bellenguez and Ried, {Janina S.} and Bergen, {Arthur A.} and Thomas Meitinger and Christian Gieger and Wong, {Tien Yin} and Hewitt, {Alex W.} and Mackey, {David A.} and Simpson, {Claire L.} and Norbert Pfeiffer and Olavi P{\"a}rssinen and Baird, {Paul N.} and Veronique Vitart and Najaf Amin and {Van Duijn}, {Cornelia M.} and Bailey-Wilson, {Joan E.} and Young, {Terri L.} and Saw, {Seang Mei} and Dwight Stambolian",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41588-018-0127-7",

language = "English",

volume = "50",

pages = "834--848",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

Tedja, MS, Wojciechowski, R, Hysi, PG, Eriksson, N, Furlotte, NA, Verhoeven, VJM, Iglesias, AI, Meester-Smoor, MA, Tompson, SW, Fan, Q, Khawaja, AP, Cheng, CY, Höhn, R, Yamashiro, K, Wenocur, A, Grazal, C, Haller, T, Metspalu, A, Wedenoja, J, Jonas, JB, Wang, YX, Xie, J, Mitchell, P, Foster, PJ, Klein, BEK, Klein, R, Paterson, AD, Hosseini, SM, Shah, RL, Williams, C, Teo, YY, Tham, YC, Gupta, P, Zhao, W, Shi, Y, Saw, WY, Tai, ES, Sim, XL, Huffman, JE, Polašek, O, Hayward, C, Bencic, G, Rudan, I, Wilson, JF, The CREAM Consortium, 23andMe Research Team, UK Biobank Eye and Vision Consortium, Joshi, PK, Tsujikawa, A, Matsuda, F, Whisenhunt, KN, Zeller, T, Van Der Spek, PJ, Haak, R, Meijers-Heijboer, H, Van Leeuwen, EM, Iyengar, SK, Lass, JH, Hofman, A, Rivadeneira, F, Uitterlinden, AG, Vingerling, JR, Lehtimäki, T, Raitakari, OT, Biino, G, Concas, MP, Schwantes-An, TH, Igo, RP, Cuellar-Partida, G, Martin, NG, Craig, JE, Gharahkhani, P, Williams, KM, Nag, A, Rahi, JS, Cumberland, PM, Delcourt, C, Bellenguez, C, Ried, JS, Bergen, AA, Meitinger, T, Gieger, C, Wong, TY, Hewitt, AW, Mackey, DA, Simpson, CL, Pfeiffer, N, Pärssinen, O, Baird, PN, Vitart, V, Amin, N, Van Duijn, CM, Bailey-Wilson, JE, Young, TL, Saw, SM & Stambolian, D 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

TY - JOUR

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

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 - The CREAM Consortium

AU - 23andMe Research Team

AU - UK Biobank Eye and Vision Consortium

AU - Joshi, Peter K.

AU - Tsujikawa, Akitaka

AU - Matsuda, Fumihiko

AU - Whisenhunt, Kristina N.

AU - Zeller, Tanja

AU - Van Der Spek, Peter J.

AU - Haak, Roxanna

AU - Meijers-Heijboer, Hanne

AU - Van Leeuwen, Elisabeth M.

AU - Iyengar, Sudha K.

AU - Lass, Jonathan H.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Vingerling, Johannes R.

AU - Lehtimäki, Terho

AU - Raitakari, Olli T.

AU - Biino, Ginevra

AU - Concas, Maria Pina

AU - Schwantes-An, Tae Hwi

AU - Igo, Robert P.

AU - Cuellar-Partida, Gabriel

AU - Martin, Nicholas G.

AU - Craig, Jamie E.

AU - Gharahkhani, Puya

AU - Williams, Katie M.

AU - Nag, Abhishek

AU - Rahi, Jugnoo S.

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.

UR - http://www.scopus.com/inward/record.url?scp=85047796358&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0127-7

DO - 10.1038/s41588-018-0127-7

M3 - Article

AN - SCOPUS:85047796358

SN - 1061-4036

VL - 50

SP - 834

EP - 848

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

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