Ophthalmology (Eye & Ear Hospital) - Research Publications

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Author: Baird, Paul × Author: Mackey, David × Author: Mitchell, Paul × Author: Wong, Tien × End date: 2020 ×

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    A genome-wide association study of corneal astigmatism: The CREAM Consortium
    Shah, RL ; Li, Q ; Zhao, W ; Tedja, MS ; Tideman, JWL ; Khawaja, AP ; Fan, Q ; Yazar, S ; Williams, KM ; Verhoeven, VJM ; Xie, J ; Wang, YX ; Hess, M ; Nickels, S ; Lackner, KJ ; Parssinen, O ; Wedenoja, J ; Biino, G ; Concas, MP ; Uitterlinden, A ; Rivadeneira, F ; Jaddoe, VWV ; Hysi, PG ; Sim, X ; Tan, N ; Tham, Y-C ; Sensaki, S ; Hofman, A ; Vingerling, JR ; Jonas, JB ; Mitchell, P ; Hammond, CJ ; Hoehn, R ; Baird, PN ; Wong, T-Y ; Cheng, C-Y ; Teo, YY ; Mackey, DA ; Williams, C ; Saw, S-M ; Klaver, CCW ; Guggenheim, JA ; Bailey-Wilson, JE (MOLECULAR VISION, 2018-02-05)
    PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.
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    Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)
    Iglesias, AI ; Mishra, A ; Vitart, V ; Bykhovskaya, Y ; Hoehn, R ; Springelkamp, H ; Cuellar-Partida, G ; Gharahkhani, P ; Bailey, JNC ; Willoughby, CE ; Li, X ; Yazar, S ; Nag, A ; Khawaja, AP ; Polasek, O ; Siscovick, D ; Mitchell, P ; Tham, YC ; Haines, JL ; Kearns, LS ; Hayward, C ; Shi, Y ; van Leeuwen, EM ; Taylor, KD ; Bonnemaijer, P ; Rotter, JI ; Martin, NG ; Zeller, T ; Mills, RA ; Souzeau, E ; Staffieri, SE ; Jonas, JB ; Schmidtmann, I ; Boutin, T ; Kang, JH ; Lucas, SEM ; Wong, TY ; Beutel, ME ; Wilson, JF ; Uitterlinden, AG ; Vithana, EN ; Foster, PJ ; Hysi, PG ; Hewitt, AW ; Khor, CC ; Pasquale, LR ; Montgomery, GW ; Klaver, CCW ; Aung, T ; Pfeiffer, N ; Mackey, DA ; Hammond, CJ ; Cheng, C-Y ; Craig, JE ; Rabinowitz, YS ; Wiggs, JL ; Burdon, KP ; van Duijn, CM ; MacGregor, S ; Wang, JJ ; Rochtchina, E ; Attia, J ; Scott, R ; Holliday, EG ; Wong, TY ; Baird, PN ; Xie, J ; Inouye, M ; Viswanathan, A ; Sim, X ; Allingham, RR ; Brilliant, MH ; Budenz, DL ; Christen, WG ; Fingert, J ; Friedman, DS ; Gaasterland, D ; Gaasterland, T ; Hauser, MA ; Kraft, P ; Lee, RK ; Lichter, PR ; Liu, Y ; Loomis, SJ ; Moroi, SE ; Pericak-Vance, MA ; Realini, A ; Richards, JE ; Schuman, JS ; Scott, WK ; Singh, K ; Sit, AJ ; Vollrath, D ; Weinreb, RN ; Wollstein, G ; Zack, DJ ; Zhang, K ; Donnelly, P ; Barroso, I ; Blackwell, JM ; Bramon, E ; Brown, MA ; Casas, JP ; Corvin, A ; Deloukas, P ; Duncanson, A ; Jankowski, J ; Markus, HS ; Mathew, CG ; Palmer, CNA ; Plomin, R ; Rautanen, A ; Sawcer, SJ ; Trembath, RC ; Wood, NW ; Spencer, CCA ; Band, G ; Bellenguez, C ; Freeman, C ; Hellenthal, G ; Giannoulatou, E ; Pirinen, M ; Pearson, R ; Strange, A ; Su, Z ; Vukcevic, D ; Langford, C ; Hunt, SE ; Edkins, S ; Gwilliam, R ; Blackburn, H ; Bumpstead, SJ ; Dronov, S ; Gillman, M ; Gray, E ; Hammond, N ; Jayakumar, A ; McCann, OT ; Liddle, J ; Potter, SC ; Ravindrarajah, R ; Ricketts, M ; Waller, M ; Weston, P ; Widaa, S ; Whittaker, P (NATURE PUBLISHING GROUP, 2019-01-08)
    Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
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    Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error
    Fan, Q ; Pozarickij, A ; Tan, NYQ ; Guo, X ; Verhoeven, VJM ; Vitart, V ; Guggenheim, JA ; Miyake, M ; Tideman, JWL ; Khawaja, AP ; Zhang, L ; MacGregor, S ; Hoehn, R ; Chen, P ; Biino, G ; Wedenoja, J ; Saffari, SE ; Tedja, MS ; Xie, J ; Lanca, C ; Wang, YX ; Sahebjada, S ; Mazur, J ; Mirshahi, A ; Martin, NG ; Yazar, S ; Pennell, CE ; Yap, M ; Haarman, AEG ; Enthoven, CA ; Polling, J ; Hewitt, AW ; Jaddoe, VWV ; van Duijn, CM ; Hayward, C ; Polasek, O ; Tai, E-S ; Yoshikatsu, H ; Hysi, PG ; Young, TL ; Tsujikawa, A ; Wang, JJ ; Mitchell, P ; Pfeiffer, N ; Parssinen, O ; Foster, PJ ; Fossarello, M ; Yip, SP ; Williams, C ; Hammond, CJ ; Jonas, JB ; He, M ; Mackey, DA ; Wong, T-Y ; Klaver, CCW ; Saw, S-M ; Baird, PN ; Cheng, C-Y (NATURE PORTFOLIO, 2020-03-19)
    Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.