Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Ching Yu Cheng; Maria Schache; M. Kamran Ikram; Terri L. Young; Jeremy A. Guggenheim; Veronique Vitart; Stuart MacGregor; Virginie J.M. Verhoeven; Veluchamy A. Barathi; Jiemin Liao; Pirro G. Hysi; Joan E. Bailey-Wilson; Beate St. Pourcain; John P. Kemp; George McMahon; Nicholas J. Timpson; David M. Evans; Grant W. Montgomery; Aniket Mishra; Ya Xing Wang; Jie Jin Wang; Elena Rochtchina; Ozren Polasek; Alan F. Wright; Najaf Amin; Elisabeth M. Van Leeuwen; James F. Wilson; Craig E. Pennell; Cornelia M. Van Duijn; Paulus T.V.M. De Jong; Johannes R. Vingerling; Xin Zhou; Peng Chen; Ruoying Li; Wan Ting Tay; Yingfeng Zheng; Merwyn Chew; Kathryn P. Burdon; Jamie E. Craig; Sudha K. Iyengar; Robert P. Igo; Jonathan H. Lass; Emily Y. Chew; Toomas Haller; Evelin Mihailov; Andres Metspalu; Juho Wedenoja; Claire L. Simpson; Robert Wojciechowski; René Höhn; Alireza Mirshahi; Tanja Zeller; Norbert Pfeiffer; Karl J. Lackner; Thomas Bettecken; Thomas Meitinger; Konrad Oexle; Mario Pirastu; Laura Portas; Abhishek Nag; Katie M. Williams; Ekaterina Yonova-Doing; Ronald Klein; Barbara E. Klein; S. Mohsen Hosseini; Andrew D. Paterson; Kari Matti Makela; Terho Lehtimaki; Mika Kahonen; Olli Raitakari; Nagahisa Yoshimura; Fumihiko Matsuda; Li Jia Chen; Chi Pui Pang; Shea Ping Yip; Maurice K.H. Yap; Akira Meguro; Nobuhisa Mizuki; Hidetoshi Inoko; Paul J. Foster; Jing Hua Zhao; Eranga Vithana; E. Shyong Tai; Qiao Fan; Liang Xu; Harry Campbell; Brian Fleck; Igor Rudan; Tin Aung; Albert Hofman; André G. Uitterlinden; Goran Bencic; Chiea Chuen Khor; Hannah Forward; Olavi Pärssinen; Paul Mitchell; Fernando Rivadeneira; Alex W. Hewitt; Cathy Williams; Ben A. Oostra; Yik Ying Teo; Christopher J. Hammond; Dwight Stambolian; David A. MacKey; Caroline C.W. Klaver; Tien Yin Wong; Seang Mei Saw; Paul N. Baird

doi:10.1016/j.ajhg.2013.06.016

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Ching Yu Cheng, Maria Schache, M. Kamran Ikram, Terri L. Young, Jeremy A. Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J.M. Verhoeven, Veluchamy A. Barathi, Jiemin Liao, Pirro G. Hysi, Joan E. Bailey-Wilson, Beate St. Pourcain, John P. Kemp, George McMahon, Nicholas J. Timpson, David M. Evans, Grant W. Montgomery, Aniket Mishra, Ya Xing WangJie Jin Wang, Elena Rochtchina, Ozren Polasek, Alan F. Wright, Najaf Amin, Elisabeth M. Van Leeuwen, James F. Wilson, Craig E. Pennell, Cornelia M. Van Duijn, Paulus T.V.M. De Jong, Johannes R. Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan Ting Tay, Yingfeng Zheng, Merwyn Chew, Kathryn P. Burdon, Jamie E. Craig, Sudha K. Iyengar, Robert P. Igo, Jonathan H. Lass, Emily Y. Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L. Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J. Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M. Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E. Klein, S. Mohsen Hosseini, Andrew D. Paterson, Kari Matti Makela, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K.H. Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J. Foster, Jing Hua Zhao, Eranga Vithana, E. Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G. Uitterlinden, Goran Bencic, Chiea Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W. Hewitt, Cathy Williams, Ben A. Oostra, Yik Ying Teo, Christopher J. Hammond, Dwight Stambolian, David A. MacKey, Caroline C.W. Klaver, Tien Yin Wong, Seang Mei Saw, Paul N. Baird

School of Medicine

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Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Original language	English (US)
Pages (from-to)	264-277
Number of pages	14
Journal	American journal of human genetics
Volume	93
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2013.06.016
State	Published - Aug 8 2013

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Cheng, C. Y., Schache, M., Ikram, M. K., Young, T. L., Guggenheim, J. A., Vitart, V., MacGregor, S., Verhoeven, V. J. M., Barathi, V. A., Liao, J., Hysi, P. G., Bailey-Wilson, J. E., St. Pourcain, B., Kemp, J. P., McMahon, G., Timpson, N. J., Evans, D. M., Montgomery, G. W., Mishra, A., ... Baird, P. N. (2013). Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error. American journal of human genetics, 93(2), 264-277. https://doi.org/10.1016/j.ajhg.2013.06.016

Cheng, CY, Schache, M, Ikram, MK, Young, TL, Guggenheim, JA, Vitart, V, MacGregor, S, Verhoeven, VJM, Barathi, VA, Liao, J, Hysi, PG, Bailey-Wilson, JE, St. Pourcain, B, Kemp, JP, McMahon, G, Timpson, NJ, Evans, DM, Montgomery, GW, Mishra, A, Wang, YX, Wang, JJ, Rochtchina, E, Polasek, O, Wright, AF, Amin, N, Van Leeuwen, EM, Wilson, JF, Pennell, CE, Van Duijn, CM, De Jong, PTVM, Vingerling, JR, Zhou, X, Chen, P, Li, R, Tay, WT, Zheng, Y, Chew, M, Burdon, KP, Craig, JE, Iyengar, SK, Igo, RP, Lass, JH, Chew, EY, Haller, T, Mihailov, E, Metspalu, A, Wedenoja, J, Simpson, CL, Wojciechowski, R, Höhn, R, Mirshahi, A, Zeller, T, Pfeiffer, N, Lackner, KJ, Bettecken, T, Meitinger, T, Oexle, K, Pirastu, M, Portas, L, Nag, A, Williams, KM, Yonova-Doing, E, Klein, R, Klein, BE, Hosseini, SM, Paterson, AD, Makela, KM, Lehtimaki, T, Kahonen, M, Raitakari, O, Yoshimura, N, Matsuda, F, Chen, LJ, Pang, CP, Yip, SP, Yap, MKH, Meguro, A, Mizuki, N, Inoko, H, Foster, PJ, Zhao, JH, Vithana, E, Tai, ES, Fan, Q, Xu, L, Campbell, H, Fleck, B, Rudan, I, Aung, T, Hofman, A, Uitterlinden, AG, Bencic, G, Khor, CC, Forward, H, Pärssinen, O, Mitchell, P, Rivadeneira, F, Hewitt, AW, Williams, C, Oostra, BA, Teo, YY, Hammond, CJ, Stambolian, D, MacKey, DA, Klaver, CCW, Wong, TY, Saw, SM & Baird, PN 2013, 'Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error', American journal of human genetics, vol. 93, no. 2, pp. 264-277. https://doi.org/10.1016/j.ajhg.2013.06.016

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title = "Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error",

abstract = "Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.",

author = "Cheng, {Ching Yu} and Maria Schache and Ikram, {M. Kamran} and Young, {Terri L.} and Guggenheim, {Jeremy A.} and Veronique Vitart and Stuart MacGregor and Verhoeven, {Virginie J.M.} and Barathi, {Veluchamy A.} and Jiemin Liao and Hysi, {Pirro G.} and Bailey-Wilson, {Joan E.} and {St. Pourcain}, Beate and Kemp, {John P.} and George McMahon and Timpson, {Nicholas J.} and Evans, {David M.} and Montgomery, {Grant W.} and Aniket Mishra and Wang, {Ya Xing} and Wang, {Jie Jin} and Elena Rochtchina and Ozren Polasek and Wright, {Alan F.} and Najaf Amin and {Van Leeuwen}, {Elisabeth M.} and Wilson, {James F.} and Pennell, {Craig E.} and {Van Duijn}, {Cornelia M.} and {De Jong}, {Paulus T.V.M.} and Vingerling, {Johannes R.} and Xin Zhou and Peng Chen and Ruoying Li and Tay, {Wan Ting} and Yingfeng Zheng and Merwyn Chew and Burdon, {Kathryn P.} and Craig, {Jamie E.} and Iyengar, {Sudha K.} and Igo, {Robert P.} and Lass, {Jonathan H.} and Chew, {Emily Y.} and Toomas Haller and Evelin Mihailov and Andres Metspalu and Juho Wedenoja and Simpson, {Claire L.} and Robert Wojciechowski and Ren{\'e} H{\"o}hn and Alireza Mirshahi and Tanja Zeller and Norbert Pfeiffer and Lackner, {Karl J.} and Thomas Bettecken and Thomas Meitinger and Konrad Oexle and Mario Pirastu and Laura Portas and Abhishek Nag and Williams, {Katie M.} and Ekaterina Yonova-Doing and Ronald Klein and Klein, {Barbara E.} and Hosseini, {S. Mohsen} and Paterson, {Andrew D.} and Makela, {Kari Matti} and Terho Lehtimaki and Mika Kahonen and Olli Raitakari and Nagahisa Yoshimura and Fumihiko Matsuda and Chen, {Li Jia} and Pang, {Chi Pui} and Yip, {Shea Ping} and Yap, {Maurice K.H.} and Akira Meguro and Nobuhisa Mizuki and Hidetoshi Inoko and Foster, {Paul J.} and Zhao, {Jing Hua} and Eranga Vithana and Tai, {E. Shyong} and Qiao Fan and Liang Xu and Harry Campbell and Brian Fleck and Igor Rudan and Tin Aung and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and Goran Bencic and Khor, {Chiea Chuen} and Hannah Forward and Olavi P{\"a}rssinen and Paul Mitchell and Fernando Rivadeneira and Hewitt, {Alex W.} and Cathy Williams and Oostra, {Ben A.} and Teo, {Yik Ying} and Hammond, {Christopher J.} and Dwight Stambolian and MacKey, {David A.} and Klaver, {Caroline C.W.} and Wong, {Tien Yin} and Saw, {Seang Mei} and Baird, {Paul N.}",

year = "2013",

month = aug,

day = "8",

doi = "10.1016/j.ajhg.2013.06.016",

language = "English (US)",

volume = "93",

pages = "264--277",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

AU - Cheng, Ching Yu

AU - Schache, Maria

AU - Ikram, M. Kamran

AU - Young, Terri L.

AU - Guggenheim, Jeremy A.

AU - Vitart, Veronique

AU - MacGregor, Stuart

AU - Verhoeven, Virginie J.M.

AU - Barathi, Veluchamy A.

AU - Liao, Jiemin

AU - Hysi, Pirro G.

AU - Bailey-Wilson, Joan E.

AU - St. Pourcain, Beate

AU - Kemp, John P.

AU - McMahon, George

AU - Timpson, Nicholas J.

AU - Evans, David M.

AU - Montgomery, Grant W.

AU - Mishra, Aniket

AU - Wang, Ya Xing

AU - Wang, Jie Jin

AU - Rochtchina, Elena

AU - Polasek, Ozren

AU - Wright, Alan F.

AU - Amin, Najaf

AU - Van Leeuwen, Elisabeth M.

AU - Wilson, James F.

AU - Pennell, Craig E.

AU - Van Duijn, Cornelia M.

AU - De Jong, Paulus T.V.M.

AU - Vingerling, Johannes R.

AU - Zhou, Xin

AU - Chen, Peng

AU - Li, Ruoying

AU - Tay, Wan Ting

AU - Zheng, Yingfeng

AU - Chew, Merwyn

AU - Burdon, Kathryn P.

AU - Craig, Jamie E.

AU - Iyengar, Sudha K.

AU - Igo, Robert P.

AU - Lass, Jonathan H.

AU - Chew, Emily Y.

AU - Haller, Toomas

AU - Mihailov, Evelin

AU - Metspalu, Andres

AU - Wedenoja, Juho

AU - Simpson, Claire L.

AU - Wojciechowski, Robert

AU - Höhn, René

AU - Mirshahi, Alireza

AU - Zeller, Tanja

AU - Pfeiffer, Norbert

AU - Lackner, Karl J.

AU - Bettecken, Thomas

AU - Meitinger, Thomas

AU - Oexle, Konrad

AU - Pirastu, Mario

AU - Portas, Laura

AU - Nag, Abhishek

AU - Williams, Katie M.

AU - Yonova-Doing, Ekaterina

AU - Klein, Ronald

AU - Klein, Barbara E.

AU - Hosseini, S. Mohsen

AU - Paterson, Andrew D.

AU - Makela, Kari Matti

AU - Lehtimaki, Terho

AU - Kahonen, Mika

AU - Raitakari, Olli

AU - Yoshimura, Nagahisa

AU - Matsuda, Fumihiko

AU - Chen, Li Jia

AU - Pang, Chi Pui

AU - Yip, Shea Ping

AU - Yap, Maurice K.H.

AU - Meguro, Akira

AU - Mizuki, Nobuhisa

AU - Inoko, Hidetoshi

AU - Foster, Paul J.

AU - Zhao, Jing Hua

AU - Vithana, Eranga

AU - Tai, E. Shyong

AU - Fan, Qiao

AU - Xu, Liang

AU - Campbell, Harry

AU - Fleck, Brian

AU - Rudan, Igor

AU - Aung, Tin

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Bencic, Goran

AU - Khor, Chiea Chuen

AU - Forward, Hannah

AU - Pärssinen, Olavi

AU - Mitchell, Paul

AU - Rivadeneira, Fernando

AU - Hewitt, Alex W.

AU - Williams, Cathy

AU - Oostra, Ben A.

AU - Teo, Yik Ying

AU - Hammond, Christopher J.

AU - Stambolian, Dwight

AU - MacKey, David A.

AU - Klaver, Caroline C.W.

AU - Wong, Tien Yin

AU - Saw, Seang Mei

AU - Baird, Paul N.

PY - 2013/8/8

Y1 - 2013/8/8

N2 - Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

AB - Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

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DO - 10.1016/j.ajhg.2013.06.016

M3 - Article

C2 - 24144296

AN - SCOPUS:84881647995

SN - 0002-9297

VL - 93

SP - 264

EP - 277

JO - American journal of human genetics

JF - American journal of human genetics

IS - 2

ER -

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

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