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; Tin Aung; Amutha B. Veluchamy; Kathryn P. Burdon; Harry Campbell; Li Jia Chen; Peng Chen; Wei Chen; Emily Chew; Margaret M. Deangelis; Xiaohu Ding; Angela Döring; David M. Evans; Sheng Feng; Brian Fleck; Rhys D. Fogarty; Jeremy R. Fondran; Maurizio Fossarello; Xiaobo Guo; Annet E.G. Haarman; Mingguang He; Laura D. Howe; Sarayut Janmahasatian; Vishal Jhanji; Mika Kähönen; Jaakko Kaprio; John P. Kemp; Kay Tee Khaw; Chiea Chuen Khor; Eva Krapohl

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, Tin Aung, Amutha B. Veluchamy, Kathryn P. Burdon, Harry Campbell, Li Jia Chen, Peng Chen, Wei Chen, Emily Chew, Margaret M. Deangelis, Xiaohu Ding, Angela Döring, David M. Evans, Sheng Feng, Brian Fleck, Rhys D. Fogarty, Jeremy R. Fondran, Maurizio Fossarello, Xiaobo Guo, Annet E.G. Haarman, Mingguang He, Laura D. Howe, Sarayut Janmahasatian, Vishal Jhanji, Mika Kähönen, Jaakko Kaprio, John P. Kemp, Kay Tee Khaw, Chiea Chuen Khor, Eva Krapohl

Research output: Journal article publication › Journal article › Academic research › peer-review

78 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 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

ASJC Scopus subject areas

Genetics

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10.1038/s41588-018-0127-7

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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., ... Krapohl, E. (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

Tedja, Milly S. ; Wojciechowski, Robert ; Hysi, Pirro G. ; Eriksson, Nicholas ; Furlotte, Nicholas A. ; Verhoeven, Virginie J.M. ; Iglesias, Adriana I. ; Meester-Smoor, Magda A. ; Tompson, Stuart W. ; Fan, Qiao ; Khawaja, Anthony P. ; Cheng, Ching Yu ; Höhn, René ; Yamashiro, Kenji ; Wenocur, Adam ; Grazal, Clare ; Haller, Toomas ; Metspalu, Andres ; Wedenoja, Juho ; Jonas, Jost B. ; Wang, Ya Xing ; Xie, Jing ; Mitchell, Paul ; Foster, Paul J. ; Klein, Barbara E.K. ; Klein, Ronald ; Paterson, Andrew D. ; Hosseini, S. Mohsen ; Shah, Rupal L. ; Williams, Cathy ; Teo, Yik Ying ; Tham, Yih Chung ; Gupta, Preeti ; Zhao, Wanting ; Shi, Yuan ; Saw, Woei Yuh ; Tai, E. Shyong ; Sim, Xue Ling ; Huffman, Jennifer E. ; Polašek, Ozren ; Hayward, Caroline ; Bencic, Goran ; Rudan, Igor ; Wilson, James F. ; Aung, Tin ; Veluchamy, Amutha B. ; Burdon, Kathryn P. ; Campbell, Harry ; Chen, Li Jia ; Chen, Peng ; Chen, Wei ; Chew, Emily ; Deangelis, Margaret M. ; Ding, Xiaohu ; Döring, Angela ; Evans, David M. ; Feng, Sheng ; Fleck, Brian ; Fogarty, Rhys D. ; Fondran, Jeremy R. ; Fossarello, Maurizio ; Guo, Xiaobo ; Haarman, Annet E.G. ; He, Mingguang ; Howe, Laura D. ; Janmahasatian, Sarayut ; Jhanji, Vishal ; Kähönen, Mika ; Kaprio, Jaakko ; Kemp, John P. ; Khaw, Kay Tee ; Khor, Chiea Chuen ; Krapohl, Eva. / 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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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 Tin Aung and Veluchamy, {Amutha B.} and Burdon, {Kathryn P.} and Harry Campbell and Chen, {Li Jia} and Peng Chen and Wei Chen and Emily Chew and Deangelis, {Margaret M.} and Xiaohu Ding and Angela D{\"o}ring and Evans, {David M.} and Sheng Feng and Brian Fleck and Fogarty, {Rhys D.} and Fondran, {Jeremy R.} and Maurizio Fossarello and Xiaobo Guo and Haarman, {Annet E.G.} and Mingguang He and Howe, {Laura D.} and Sarayut Janmahasatian and Vishal Jhanji and Mika K{\"a}h{\"o}nen and Jaakko Kaprio and Kemp, {John P.} and Khaw, {Kay Tee} and Khor, {Chiea Chuen} and Eva Krapohl",

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

language = "English",

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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, Aung, T, Veluchamy, AB, Burdon, KP, Campbell, H, Chen, LJ, Chen, P, Chen, W, Chew, E, Deangelis, MM, Ding, X, Döring, A, Evans, DM, Feng, S, Fleck, B, Fogarty, RD, Fondran, JR, Fossarello, M, Guo, X, Haarman, AEG, He, M, Howe, LD, Janmahasatian, S, Jhanji, V, Kähönen, M, Kaprio, J, Kemp, JP, Khaw, KT, Khor, CC & Krapohl, E 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. / Tedja, Milly S.; Wojciechowski, Robert; Hysi, Pirro G.; Eriksson, Nicholas; Furlotte, Nicholas A.; Verhoeven, Virginie J.M.; Iglesias, Adriana I.; Meester-Smoor, Magda A.; Tompson, Stuart W.; Fan, Qiao; Khawaja, Anthony P.; Cheng, Ching Yu; Höhn, René; Yamashiro, Kenji; Wenocur, Adam; Grazal, Clare; Haller, Toomas; Metspalu, Andres; Wedenoja, Juho; Jonas, Jost B.; Wang, Ya Xing; Xie, Jing; Mitchell, Paul; Foster, Paul J.; Klein, Barbara E.K.; Klein, Ronald; Paterson, Andrew D.; Hosseini, S. Mohsen; Shah, Rupal L.; Williams, Cathy; Teo, Yik Ying; Tham, Yih Chung; Gupta, Preeti; Zhao, Wanting; Shi, Yuan; Saw, Woei Yuh; Tai, E. Shyong; Sim, Xue Ling; Huffman, Jennifer E.; Polašek, Ozren; Hayward, Caroline; Bencic, Goran; Rudan, Igor; Wilson, James F.; Aung, Tin; Veluchamy, Amutha B.; Burdon, Kathryn P.; Campbell, Harry; Chen, Li Jia; Chen, Peng; Chen, Wei; Chew, Emily; Deangelis, Margaret M.; Ding, Xiaohu; Döring, Angela; Evans, David M.; Feng, Sheng; Fleck, Brian; Fogarty, Rhys D.; Fondran, Jeremy R.; Fossarello, Maurizio; Guo, Xiaobo; Haarman, Annet E.G.; He, Mingguang; Howe, Laura D.; Janmahasatian, Sarayut; Jhanji, Vishal; Kähönen, Mika; Kaprio, Jaakko; Kemp, John P.; Khaw, Kay Tee; Khor, Chiea Chuen; Krapohl, Eva.

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

Research output: Journal article publication › Journal article › Academic research › peer-review

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 - 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.

AU - Fondran, Jeremy R.

AU - Fossarello, Maurizio

AU - Guo, Xiaobo

AU - Haarman, Annet E.G.

AU - He, Mingguang

AU - Howe, Laura D.

AU - Janmahasatian, Sarayut

AU - Jhanji, Vishal

AU - Kähönen, Mika

AU - Kaprio, Jaakko

AU - Kemp, John P.

AU - Khaw, Kay Tee

AU - Khor, Chiea Chuen

AU - Krapohl, Eva

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 - Journal article

VL - 50

SP - 834

EP - 848

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -

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

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