Ophthalmology (Eye & Ear Hospital) - Research Publications

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    A saturated map of common genetic variants associated with human height
    Yengo, L ; Vedantam, S ; Marouli, E ; Sidorenko, J ; Bartell, E ; Sakaue, S ; Graff, M ; Eliasen, AU ; Jiang, Y ; Raghavan, S ; Miao, J ; Arias, JD ; Graham, SE ; Mukamel, RE ; Spracklen, CN ; Yin, X ; Chen, S-H ; Ferreira, T ; Highland, HH ; Ji, Y ; Karaderi, T ; Lin, K ; Lull, K ; Malden, DE ; Medina-Gomez, C ; Machado, M ; Moore, A ; Rueger, S ; Sim, X ; Vrieze, S ; Ahluwalia, TS ; Akiyama, M ; Allison, MA ; Alvarez, M ; Andersen, MK ; Ani, A ; Appadurai, V ; Arbeeva, L ; Bhaskar, S ; Bielak, LF ; Bollepalli, S ; Bonnycastle, LL ; Bork-Jensen, J ; Bradfield, JP ; Bradford, Y ; Braund, PS ; Brody, JA ; Burgdorf, KS ; Cade, BE ; Cai, H ; Cai, Q ; Campbell, A ; Canadas-Garre, M ; Catamo, E ; Chai, J-F ; Chai, X ; Chang, L-C ; Chang, Y-C ; Chen, C-H ; Chesi, A ; Choi, SH ; Chung, R-H ; Cocca, M ; Concas, MP ; Couture, C ; Cuellar-Partida, G ; Danning, R ; Daw, EW ; Degenhard, F ; Delgado, GE ; Delitala, A ; Demirkan, A ; Deng, X ; Devineni, P ; Dietl, A ; Dimitriou, M ; Dimitrov, L ; Dorajoo, R ; Ekici, AB ; Engmann, JE ; Fairhurst-Hunter, Z ; Farmaki, A-E ; Faul, JD ; Fernandez-Lopez, J-C ; Forer, L ; Francescatto, M ; Freitag-Wolf, S ; Fuchsberger, C ; Galesloot, TE ; Gao, Y ; Gao, Z ; Geller, F ; Giannakopoulou, O ; Giulianini, F ; Gjesing, AP ; Goel, A ; Gordon, SD ; Gorski, M ; Grove, J ; Guo, X ; Gustafsson, S ; Haessler, J ; Hansen, TF ; Havulinna, AS ; Haworth, SJ ; He, J ; Heard-Costa, N ; Hebbar, P ; Hindy, G ; Ho, Y-LA ; Hofer, E ; Holliday, E ; Horn, K ; Hornsby, WE ; Hottenga, J-J ; Huang, H ; Huang, J ; Huerta-Chagoya, A ; Huffman, JE ; Hung, Y-J ; Huo, S ; Hwang, MY ; Iha, H ; Ikeda, DD ; Isono, M ; Jackson, AU ; Jager, S ; Jansen, IE ; Johansson, I ; Jonas, JB ; Jonsson, A ; Jorgensen, T ; Kalafati, I-P ; Kanai, M ; Kanoni, S ; Karhus, LL ; Kasturiratne, A ; Katsuya, T ; Kawaguchi, T ; Kember, RL ; Kentistou, KA ; Kim, H-N ; Kim, YJ ; Kleber, ME ; Knol, MJ ; Kurbasic, A ; Lauzon, M ; Le, P ; Lea, R ; Lee, J-Y ; Leonard, HL ; Li, SA ; Li, X ; Li, X ; Liang, J ; Lin, H ; Lin, S-Y ; Liu, J ; Liu, X ; Lo, KS ; Long, J ; Lores-Motta, L ; Luan, J ; Lyssenko, V ; Lyytikainen, L-P ; Mahajan, A ; Mamakou, V ; Mangino, M ; Manichaikul, A ; Marten, J ; Mattheisen, M ; Mavarani, L ; McDaid, AF ; Meidtner, K ; Melendez, TL ; Mercader, JM ; Milaneschi, Y ; Miller, JE ; Millwood, IY ; Mishra, PP ; Mitchell, RE ; Mollehave, LT ; Morgan, A ; Mucha, S ; Munz, M ; Nakatochi, M ; Nelson, CP ; Nethander, M ; Nho, CW ; Nielsen, AA ; Nolte, IM ; Nongmaithem, SS ; Noordam, R ; Ntalla, I ; Nutile, T ; Pandit, A ; Christofidou, P ; Parna, K ; Pauper, M ; Petersen, ERB ; Petersen, L ; Pitkanen, N ; Polasek, O ; Poveda, A ; Preuss, MH ; Pyarajan, S ; Raffield, LM ; Rakugi, H ; Ramirez, J ; Rasheed, A ; Raven, D ; Rayner, NW ; Riveros, C ; Rohde, R ; Ruggiero, D ; Ruotsalainen, SE ; Ryan, KA ; Sabater-Lleal, M ; Saxena, R ; Scholz, M ; Sendamarai, A ; Shen, B ; Shi, J ; Shin, JH ; Sidore, C ; Sitlani, CM ; Slieker, RKC ; Smit, RAJ ; Smith, A ; Smith, JA ; Smyth, LJ ; Southam, LE ; Steinthorsdottir, V ; Sun, L ; Takeuchi, F ; Tallapragada, D ; Taylor, KD ; Tayo, BO ; Tcheandjieu, C ; Terzikhan, N ; Tesolin, P ; Teumer, A ; Theusch, E ; Thompson, DJ ; Thorleifsson, G ; Timmers, PRHJ ; Trompet, S ; Turman, C ; Vaccargiu, S ; van der Laan, SW ; van der Most, PJ ; van Klinken, JB ; van Setten, J ; Verma, SS ; Verweij, N ; Veturi, Y ; Wang, CA ; Wang, C ; Wang, L ; Wang, Z ; Warren, HR ; Wei, WB ; Wickremasinghe, AR ; Wielscher, M ; Wiggins, KL ; Winsvold, BS ; Wong, A ; Wu, Y ; Wuttke, M ; Xia, R ; Xie, T ; Yamamoto, K ; Yang, J ; Yao, J ; Young, H ; Yousri, NA ; Yu, L ; Zeng, L ; Zhang, W ; Zhang, X ; Zhao, J-H ; Zhao, W ; Zhou, W ; Zimmermann, ME ; Zoledziewska, M ; Adair, LS ; Adams, HHH ; Aguilar-Salinas, CA ; Al-Mulla, F ; Arnett, DK ; Asselbergs, FW ; Asvold, BO ; Attia, J ; Banas, B ; Bandinelli, S ; Bennett, DA ; Bergler, T ; Bharadwaj, D ; Biino, G ; Bisgaard, H ; Boerwinkle, E ; Boger, CA ; Bonnelykke, K ; Boomsma, D ; Borglum, AD ; Borja, JB ; Bouchard, C ; Bowden, DW ; Brandslund, I ; Brumpton, B ; Buring, JE ; Caulfield, MJ ; Chambers, JC ; Chandak, GR ; Chanock, SJ ; Chaturvedi, N ; Chen, Y-DI ; Chen, Z ; Cheng, C-Y ; Christophersen, IE ; Ciullo, M ; Cole, JW ; Collins, FS ; Cooper, RS ; Cruz, M ; Cucca, F ; Cupples, LA ; Cutler, MJ ; Damrauer, SM ; Dantoft, TM ; de Borst, GJ ; de Groot, LCPGM ; De Jager, PL ; de Kleijn, DP ; de Silva, HJ ; Dedoussis, G ; den Hollander, A ; Du, S ; Easton, DF ; Elders, PJM ; Eliassen, AH ; Ellinor, PT ; Elmstahl, S ; Erdmann, J ; Evans, MK ; Fatkin, D ; Feenstra, B ; Feitosa, MF ; Ferrucci, L ; Ford, I ; Fornage, M ; Franke, A ; Franks, PW ; Freedman, B ; Gasparini, P ; Gieger, C ; Girotto, G ; Goddard, ME ; Golightly, YM ; Gonzalez-Villalpando, C ; Gordon-Larsen, P ; Grallert, H ; Grant, SFA ; Grarup, N ; Griffiths, L ; Gudnason, V ; Haiman, C ; Hakonarson, H ; Hansen, T ; Hartman, CA ; Hattersley, AT ; Hayward, C ; Heckbert, SR ; Heng, C-K ; Hengstenberg, C ; Hewitt, AW ; Hishigaki, H ; Hoyng, CB ; Huang, PL ; Huang, W ; Hunt, SC ; Hveem, K ; Hypponen, E ; Iacono, WG ; Ichihara, S ; Ikram, MA ; Isasi, CR ; Jackson, RD ; Jarvelin, M-R ; Jin, Z-B ; Jockel, K-H ; Joshi, PK ; Jousilahti, P ; Jukema, JW ; Kahonen, M ; Kamatani, Y ; Kang, KD ; Kaprio, J ; Kardia, SLR ; Karpe, F ; Kato, N ; Kee, F ; Kessler, T ; Khera, A ; Khor, CC ; Kiemeney, LALM ; Kim, B-J ; Kim, EK ; Kim, H-L ; Kirchhof, P ; Kivimaki, M ; Koh, W-P ; Koistinen, HA ; Kolovou, GD ; Kooner, JS ; Kooperberg, C ; Kottgen, A ; Kovacs, P ; Kraaijeveld, A ; Kraft, P ; Krauss, RM ; Kumari, M ; Kutalik, Z ; Laakso, M ; Lange, LA ; Langenberg, C ; Launer, LJ ; Le Marchand, L ; Lee, H ; Lee, NR ; Lehtimaki, T ; Li, H ; Li, L ; Lieb, W ; Lin, X ; Lind, L ; Linneberg, A ; Liu, C-T ; Liu, J ; Loeffler, M ; London, B ; Lubitz, SA ; Lye, SJ ; Mackey, DA ; Magi, R ; Magnusson, PKE ; Marcus, GM ; Vidal, PM ; Martin, NG ; Marz, W ; Matsuda, F ; McGarrah, RW ; McGue, M ; McKnight, AJ ; Medland, SE ; Mellstrom, D ; Metspalu, A ; Mitchell, BD ; Mitchell, P ; Mook-Kanamori, DO ; Morris, AD ; Mucci, LA ; Munroe, PB ; Nalls, MA ; Nazarian, S ; Nelson, AE ; Neville, MJ ; Newton-Cheh, C ; Nielsen, CS ; Nothen, MM ; Ohlsson, C ; Oldehinkel, AJ ; Orozco, L ; Pahkala, K ; Pajukanta, P ; Palmer, CNA ; Parra, EJ ; Pattaro, C ; Pedersen, O ; Pennell, CE ; Penninx, BWJH ; Perusse, L ; Peters, A ; Peyser, PA ; Porteous, DJ ; Posthuma, D ; Power, C ; Pramstaller, PP ; Province, MA ; Qi, Q ; Qu, J ; Rader, DJ ; Raitakari, OT ; Ralhan, S ; Rallidis, LS ; Rao, DC ; Redline, S ; Reilly, DF ; Reiner, AP ; Rhee, SY ; Ridker, PM ; Rienstra, M ; Ripatti, S ; Ritchie, MD ; Roden, DM ; Rosendaal, FR ; Rotter, J ; Rudan, I ; Rutters, F ; Sabanayagam, C ; Saleheen, D ; Salomaa, V ; Samani, NJ ; Sanghera, DK ; Sattar, N ; Schmidt, B ; Schmidt, H ; Schmidt, R ; Schulze, MB ; Schunkert, H ; Scott, LJ ; Scott, RJ ; Sever, P ; Shiroma, EJ ; Shoemaker, MB ; Shu, X-O ; Simonsick, EM ; Sims, M ; Singh, JR ; Singleton, AB ; Sinner, MF ; Smith, JG ; Snieder, H ; Spector, TD ; Stampfer, MJ ; Stark, KJ ; Strachan, DP ; t' Hart, LM ; Tabara, Y ; Tang, H ; Tardif, J-C ; Thanaraj, TA ; Timpson, NJ ; Tonjes, A ; Tremblay, A ; Tuomi, T ; Tuomilehto, J ; Tusie-Luna, M-T ; Uitterlinden, AG ; van Dam, RM ; van der Harst, P ; Van der Velde, N ; van Duijn, CM ; van Schoor, NM ; Vitart, V ; Volker, U ; Vollenweider, P ; Volzke, H ; Wacher-Rodarte, NH ; Walker, M ; Wang, YX ; Wareham, NJ ; Watanabe, RM ; Watkins, H ; Weir, DR ; Werge, TM ; Widen, E ; Wilkens, LR ; Willemsen, G ; Willett, WC ; Wilson, JF ; Wong, T-Y ; Woo, J-T ; Wright, AF ; Wu, J-Y ; Xu, H ; Yajnik, CS ; Yokota, M ; Yuan, J-M ; Zeggini, E ; Zemel, BS ; Zheng, W ; Zhu, X ; Zmuda, JM ; Zonderman, AB ; Zwart, J-A ; Chasman, D ; Cho, YS ; Heid, IM ; McCarthy, M ; Ng, MCY ; O'Donnell, CJ ; Rivadeneira, F ; Thorsteinsdottir, U ; Sun, Y ; Tai, ES ; Boehnke, M ; Deloukas, P ; Justice, AE ; Lindgren, CM ; Loos, RJF ; Mohlke, KL ; North, KE ; Stefansson, K ; Walters, RG ; Winkler, TW ; Young, KL ; Loh, P-R ; Yang, J ; Esko, T ; Assimes, TL ; Auton, A ; Abecasis, GR ; Willer, CJ ; Locke, AE ; Berndt, S ; Lettre, G ; Frayling, TM ; Okada, Y ; Wood, AR ; Visscher, PM ; Hirschhorn, JN (NATURE PORTFOLIO, 2022-10-27)
    Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
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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
    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 ; 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 (NATURE PUBLISHING GROUP, 2018-05-14)
    Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
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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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    Multi-trait genome-wide association study identifies new loci associated with optic disc parameters
    Bonnemaijer, PWM ; van Leeuwen, EM ; Iglesias, AI ; Gharahkhani, P ; Vitart, V ; Khawaja, AP ; Simcoe, M ; Hoehn, R ; Cree, AJ ; Igo, RP ; Burdon, KP ; Craig, JE ; Hewitt, AW ; Jonas, J ; Khor, C-C ; Pasutto, F ; Mackey, DA ; Mitchell, P ; Mishra, A ; Pang, C ; Pasquale, LR ; Springelkamp, H ; Thorleifsson, G ; Thorsteinsdottir, U ; Viswanathan, AC ; Wojciechowski, R ; Wong, T ; Young, TL ; Zeller, T ; Atan, D ; Aslam, T ; Barman, SA ; Barrett, JH ; Bishop, P ; Blows, P ; Bunce, C ; Carare, RO ; Chakravarthy, U ; Chan, M ; Chua, SYL ; Crabb, DP ; Cumberland, PM ; Day, A ; Desai, P ; Dhillon, B ; Dick, AD ; Egan, C ; Ennis, S ; Foster, P ; Fruttiger, M ; Gallacher, JEJ ; Garway, DF ; Gibson, J ; Gore, D ; Guggenheim, JA ; Hardcastle, A ; Harding, SP ; Hogg, RE ; Keane, PA ; Khaw, PT ; Lascaratos, G ; Macgillivray, T ; Mackie, S ; Martin, K ; McGaughey, M ; McGuinness, B ; Mckay, GJ ; McKibbin, M ; Mitry, D ; Moore, T ; Morgan, JE ; Muthy, ZA ; O'Sullivan, E ; Owen, CG ; Patel, P ; Paterson, E ; Peto, T ; Petzold, A ; Rahi, JS ; Rudnikca, AR ; Self, J ; Sivaprasad, S ; Steel, D ; Stratton, I ; Strouthidis, N ; Sudlow, C ; Thomas, D ; Trucco, E ; Tufail, A ; Vernon, SA ; Viswanathan, AC ; Williams, C ; Williams, K ; Woodside, JV ; Yates, MM ; Yip, J ; Zheng, Y ; Allingham, R ; Budenz, D ; Bailey, JC ; Fingert, J ; Gaasterland, D ; Gaasterland, T ; Haines, JL ; Hark, L ; Hauser, M ; Kang, JH ; Kraft, P ; Lee, R ; Lichter, P ; Liu, Y ; Moroi, S ; Pasquale, LR ; Pericak, M ; Realini, A ; Rhee, D ; Richards, JR ; Ritch, R ; Scott, WK ; Singh, K ; Sit, A ; Vollrath, D ; Weinreb, R ; Wollstein, G ; Wilmer, DZ ; Gerhold-Ay, A ; Nickels, S ; Wilson, JF ; Hayward, C ; Boutin, TS ; Polasek, O ; Aung, T ; Khor, CC ; Amin, N ; Lotery, AJ ; Wiggs, JL ; Cheng, C-Y ; Hysi, PG ; Hammond, CJ ; Thiadens, AAHJ ; MacGregor, S ; Klaver, CCW ; van Duijn, CM (NATURE PUBLISHING GROUP, 2019-11-27)
    A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
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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.