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

Lookup NU author(s): David Steel


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© 2018 The Author(s) 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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Author(s): Tedja MS, Wojciechowski R, Hysi PG, Eriksson N, Furlotte NA, Verhoeven VJM, Iglesias AI, Meester-Smoor MA, Tompson SW, Fan Q, Khawaja AP, Cheng C-Y, Hohn 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 W-Y, Tai E-S, Sim XL, Huffman JE, Polasek 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, Doring 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, Kahonen M, Kaprio J, Kemp JP, Khaw K-T, Khor C-C, Krapohl E, Korobelnik J-F, Lee K, Li S-M, Lu Y, Luben RN, Makela K-M, McMahon G, Meguro A, Mihailov E, Miyake M, Mizuki N, Morrison M, Nangia V, Oexle K, Panda-Jonas S, Pang CP, Pirastu M, Plomin R, Rantanen T, Schache M, Seppala I, Smith GD, Pourcain BS, Tam PO, Tideman JWL, Timpson NJ, Vaccargiu S, Vatavuk Z, Wang JJ, Wang N, Wareham NJ, Wright AF, Xu L, Yap MKH, Yazar S, Yip SP, Yoshimura N, Young AL, Zhao JH, Zhou X, Agee M, Alipanahi B, Auton A, Bell RK, Bryc K, Elson SL, Fontanillas P, Hinds DA, McCreight JC, Huber KE, Kleinman A, Litterman NK, McIntyre MH, Mountain JL, Noblin ES, Northover CAM, Pitts SJ, Sathirapongsasuti JF, Sazonova OV, Shelton JF, Shringarpure S, Tian C, Vacic V, Wilson CH, Aslam TM, Barman SA, Barrett JH, Bishop PN, Blows P, Bunce C, Carare RO, Chakravarthy U, Chan M, Chua S, Crabb D, Day A, Desai P, Dhillon B, Dick AD, Egan CA, Ennis S, Fruttiger M, Gallacher J, Garway-Heath DF, Gibson J, Gore DM, Hardcastle A, Harding SP, Hogg RE, Keane PA, Khaw PT, Lascaratos G, Lotery A, Luthert PJ, MacGillivray TJ, Mackie SL, Martin KR, McGaughey M, McGuinness B, McKay GJ, McKibbin M, Mitry D, Moore T, Morgan JE, Muthy ZA, O'Sullivan E, Owen C, Patel PJ, Paterson EN, Peto T, Petzold A, Rudnicka AR, Self JE, Sivaprasad S, Steel DHW, Stratton IM, Strouthidis N, Sudlow CLM, Thaung C, Thomas D, Trucco E, Tufail A, Vernon SA, Viswanathan AC, Woodside JV, Yates M, Yip JLY, Zheng Y, 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, Lehtimaki T, Raitakari OT, Biino G, Concas MP, Schwantes-An T-H, 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, Parssinen O, Baird PN, Vitart V, Amin N, van Duijn CM, Bailey-Wilson JE, Young TL, Saw S-M, Stambolian D, MacGregor S, Guggenheim JA, Tung JY, Hammond CJ, Klaver CCW

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2018

Volume: 50

Pages: 834-848

Online publication date: 28/05/2018

Acceptance date: 26/03/2018

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/s41588-018-0127-7


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