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

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 - 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

AU - MacGregor, Stuart

AU - Guggenheim, Jeremy A

AU - Tung, Joyce Y

AU - Hammond, Christopher J

AU - Klaver, Caroline C W

AU - CREAM Consortium

PY - 2018/6

Y1 - 2018/6

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.

KW - Adult

KW - Asian Continental Ancestry Group/genetics

KW - Blindness/genetics

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Male

KW - Myopia/genetics

KW - Polymorphism, Single Nucleotide

KW - Refractive Errors/genetics

KW - Retina/metabolism

KW - Retinal Pigment Epithelium/metabolism

KW - Signal Transduction

U2 - 10.1038/s41588-018-0127-7

DO - 10.1038/s41588-018-0127-7

M3 - SCORING: Journal article

C2 - 29808027

VL - 50

SP - 834

EP - 848

JO - NAT GENET

JF - NAT GENET

SN - 1061-4036

IS - 6

ER -