Centre for Eye Research Australia (CERA) - 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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    Alterations in Retinal Microvascular Geometry in Young Type 1 Diabetes
    Sasongko, MB ; Wang, JJ ; Donaghue, KC ; Cheung, N ; Benitez-Aguirre, P ; Jenkins, A ; Hsu, W ; Lee, M-L ; Wong, TY (AMER DIABETES ASSOC, 2010-06)
    OBJECTIVE: To describe retinal microvascular geometric parameters in young patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (aged 12-20 years) had clinical assessments and retinal photography following standardized protocol at a tertiary-care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length-to-diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, A1C level, systolic blood pressure (SBP), and other risk factors were assessed. RESULTS: Of 1,159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (P = 0.024) and venular (P = 0.002) tortuosity, and female subjects had larger arteriolar branching angle than male subjects (P = 0.03). After adjusting for age and sex, longer diabetes duration was associated with larger arteriolar branching angle (P 8.5 vs.
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    Quantitative Assessment of Early Diabetic Retinopathy Using Fractal Analysis
    Cheung, N ; Donaghue, KC ; Liew, G ; Rogers, SL ; Wang, JJ ; Lim, S-W ; Jenkins, AJ ; Hsu, W ; Lee, ML ; Wong, TY (AMER DIABETES ASSOC, 2009-01)
    OBJECTIVE: Fractal analysis can quantify the geometric complexity of the retinal vascular branching pattern and may therefore offer a new method to quantify early diabetic microvascular damage. In this study, we examined the relationship between retinal fractal dimension and retinopathy in young individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study of 729 patients with type 1 diabetes (aged 12-20 years) who had seven-field stereoscopic retinal photographs taken of both eyes. From these photographs, retinopathy was graded according to the modified Airlie House classification, and fractal dimension was quantified using a computer-based program following a standardized protocol. RESULTS: In this study, 137 patients (18.8%) had diabetic retinopathy signs; of these, 105 had mild retinopathy. Median (interquartile range) retinal fractal dimension was 1.46214 (1.45023-1.47217). After adjustment for age, sex, diabetes duration, A1C, blood pressure, and total cholesterol, increasing retinal vascular fractal dimension was significantly associated with increasing odds of retinopathy (odds ratio 3.92 [95% CI 2.02-7.61] for fourth versus first quartile of fractal dimension). In multivariate analysis, each 0.01 increase in retinal vascular fractal dimension was associated with a nearly 40% increased odds of retinopathy (1.37 [1.21-1.56]). This association remained after additional adjustment for retinal vascular caliber. CONCLUSIONS: Greater retinal fractal dimension, representing increased geometric complexity of the retinal vasculature, is independently associated with early diabetic retinopathy signs in type 1 diabetes. Fractal analysis of fundus photographs may allow quantitative measurement of early diabetic microvascular damage.
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    Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma
    King, R ; Struebing, FL ; Li, Y ; Wang, J ; Koch, AA ; Bailey, JNC ; Gharahkhani, P ; MacGregor, S ; Allingham, RR ; Hauser, MA ; Wiggs, JL ; Geiser, EE ; Anderson, MG (PUBLIC LIBRARY SCIENCE, 2018-01)
    Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
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    Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus
    Fan, BJ ; Chen, X ; Sondhi, N ; Sharmila, PF ; Soumittra, N ; Sripriya, S ; Sacikala, S ; Asokan, R ; Friedman, DS ; Pasquale, LR ; Gao, XR ; Vijaya, L ; Bailey, JC ; Vitart, V ; MacGregor, S ; Hammond, CJ ; Khor, CC ; Haines, JL ; George, R ; Wiggs, JL (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-05)
    PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = -0.57, 95% confidence interval [CI]: -0.78 to -0.36; P = 1.7 × 10-7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = -3.94, 95% CI: -5.23 to -2.66; P = 1.7 × 10-9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.
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    Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium
    Verhoeven, VJM ; Hysi, PG ; Saw, S-M ; Vitart, V ; Mirshahi, A ; Guggenheim, JA ; Cotch, MF ; Yamashiro, K ; Baird, PN ; Mackey, DA ; Wojciechowski, R ; Ikram, MK ; Hewitt, AW ; Duggal, P ; Janmahasatian, S ; Khor, C-C ; Fan, Q ; Zhou, X ; Young, TL ; Tai, E-S ; Goh, L-K ; Li, Y-J ; Aung, T ; Vithana, E ; Teo, Y-Y ; Tay, W ; Sim, X ; Rudan, I ; Hayward, C ; Wright, AF ; Polasek, O ; Campbell, H ; Wilson, JF ; Fleck, BW ; Nakata, I ; Yoshimura, N ; Yamada, R ; Matsuda, F ; Ohno-Matsui, K ; Nag, A ; McMahon, G ; St Pourcain, B ; Lu, Y ; Rahi, JS ; Cumberland, PM ; Bhattacharya, S ; Simpson, CL ; Atwood, LD ; Li, X ; Raffel, LJ ; Murgia, F ; Portas, L ; Despriet, DDG ; van Koolwijk, LME ; Wolfram, C ; Lackner, KJ ; Toenjes, A ; Maegi, R ; Lehtimaki, T ; Kahonen, M ; Esko, T ; Metspalu, A ; Rantanen, T ; Parssinen, O ; Klein, BE ; Meitinger, T ; Spector, TD ; Oostra, BA ; Smith, AV ; de Jong, PTVM ; Hofman, A ; Amin, N ; Karssen, LC ; Rivadeneira, F ; Vingerling, JR ; Eiriksdottir, G ; Gudnason, V ; Doering, A ; Bettecken, T ; Uitterlinden, AG ; Williams, C ; Zeller, T ; Castagne, R ; Oexle, K ; van Duijn, CM ; Iyengar, SK ; Mitchell, P ; Wang, JJ ; Hoehn, R ; Pfeiffer, N ; Bailey-Wilson, JE ; Stambolian, D ; Wong, T-Y ; Hammond, CJ ; Klaver, CCW (SPRINGER, 2012-09)
    Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
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    Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
    Bailey, JNC ; Loomis, SJ ; Kang, JH ; Allingham, RR ; Gharahkhani, P ; Khor, CC ; Burdon, KP ; Aschard, H ; Chasman, DI ; Igo, RP ; Hysi, PG ; Glastonbury, CA ; Ashley-Koch, A ; Brilliant, M ; Brown, AA ; Budenz, DL ; Buil, A ; Cheng, C-Y ; Choi, H ; Christen, WG ; Curhan, G ; De Vivo, I ; Fingert, JH ; Foster, PJ ; Fuchs, C ; Gaasterland, D ; Gaasterland, T ; Hewitt, AW ; Hu, F ; Hunter, DJ ; Khawaja, AP ; Lee, RK ; Li, Z ; Lichter, PR ; Mackey, DA ; McGuffin, P ; Mitchell, P ; Moroi, SE ; Perera, SA ; Pepper, KW ; Qi, Q ; Realini, T ; Richards, JE ; Ridker, PM ; Rimm, E ; Ritch, R ; Ritchie, M ; Schuman, JS ; Scott, WK ; Singh, K ; Sit, AJ ; Song, YE ; Tamimi, RM ; Topouzis, F ; Viswanathan, AC ; Verma, SS ; Vollrath, D ; Wang, JJ ; Weisschuh, N ; Wissinger, B ; Wollstein, G ; Wong, TY ; Yaspan, BL ; Zack, DJ ; Zhang, K ; Weinreb, RN ; Pericak-Vance, MA ; Small, K ; Hammond, CJ ; Aung, T ; Liu, Y ; Vithana, EN ; MacGregor, S ; Craig, JE ; Kraftl, P ; Howell, G ; Hauser, MA ; Pasguale, LR ; Haines, JL ; Wiggs, JL (NATURE PUBLISHING GROUP, 2016-02)
    Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
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    Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium
    Li, Q ; Wojciechowski, R ; Simpson, CL ; Hysi, PG ; Verhoeven, VJM ; Ikram, MK ; Hoehn, R ; Vitart, V ; Hewitt, AW ; Oexle, K ; Makela, K-M ; MacGregor, S ; Pirastu, M ; Fan, Q ; Cheng, C-Y ; St Pourcain, B ; McMahon, G ; Kemp, JP ; Northstone, K ; Rahi, JS ; Cumberland, PM ; Martin, NG ; Sanfilippo, PG ; Lu, Y ; Wang, YX ; Hayward, C ; Polasek, O ; Campbell, H ; Bencic, G ; Wright, AF ; Wedenoja, J ; Zeller, T ; Schillert, A ; Mirshahi, A ; Lackner, K ; Yip, SP ; Yap, MKH ; Ried, JS ; Gieger, C ; Murgia, F ; Wilson, JF ; Fleck, B ; Yazar, S ; Vingerling, JR ; Hofman, A ; Uitterlinden, A ; Rivadeneira, F ; Amin, N ; Karssen, L ; Oostra, BA ; Zhou, X ; Teo, Y-Y ; Tai, ES ; Vithana, E ; Barathi, V ; Zheng, Y ; Siantar, RG ; Neelam, K ; Shin, Y ; Lam, J ; Yonova-Doing, E ; Venturini, C ; Hosseini, SM ; Wong, H-S ; Lehtimaki, T ; Kahonen, M ; Raitakari, O ; Timpson, NJ ; Evans, DM ; Khor, C-C ; Aung, T ; Young, TL ; Mitchell, P ; Klein, B ; van Duijn, CM ; Meitinger, T ; Jonas, JB ; Baird, PN ; Mackey, DA ; Wong, TY ; Saw, S-M ; Parssinen, O ; Stambolian, D ; Hammond, CJ ; Klaver, CCW ; Williams, C ; Paterson, AD ; Bailey-Wilson, JE ; Guggenheim, JA (SPRINGER, 2015-02)
    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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    Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci
    Simpson, CL ; Wojciechowski, R ; Oexle, K ; Murgia, F ; Portas, L ; Li, X ; Verhoeven, VJM ; Vitart, V ; Schache, M ; Hosseini, SM ; Hysi, PG ; Raffel, LJ ; Cotch, MF ; Chew, E ; Klein, BEK ; Klein, R ; Wong, TY ; Van Duijn, CM ; Mitchell, P ; Saw, SM ; Fossarello, M ; Wang, JJ ; Polasek, O ; Campbell, H ; Rudan, I ; Oostra, BA ; Uitterlinden, AG ; Hofman, A ; Rivadeneira, F ; Amin, N ; Karssen, LC ; Vingerling, JR ; Doering, A ; Bettecken, T ; Bencic, G ; Gieger, C ; Wichmann, H-E ; Wilson, JF ; Venturini, C ; Fleck, B ; Cumberland, PM ; Rahi, JS ; Hammond, CJ ; Hayward, C ; Wright, AF ; Paterson, AD ; Baird, PN ; Klaver, CCW ; Rotter, JI ; Pirastu, M ; Meitinger, T ; Bailey-Wilson, JE ; Stambolian, D ; Miao, X (PUBLIC LIBRARY SCIENCE, 2014-09-18)
    Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.
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    Genetic Loci for Retinal Arteriolar Microcirculation
    Sim, X ; Jensen, RA ; Ikram, MK ; Cotch, MF ; Li, X ; MacGregor, S ; Xie, J ; Smith, AV ; Boerwinkle, E ; Mitchell, P ; Klein, R ; Klein, BEK ; Glazer, NL ; Lumley, T ; McKnight, B ; Psaty, BM ; de Jong, PTVM ; Hofman, A ; Rivadeneira, F ; Uitterlinden, AG ; van Duijn, CM ; Aspelund, T ; Eiriksdottir, G ; Harris, TB ; Jonasson, F ; Launer, LJ ; Attia, J ; Baird, PN ; Harrap, S ; Holliday, EG ; Inouye, M ; Rochtchina, E ; Scott, RJ ; Viswanathan, A ; Li, G ; Smith, NL ; Wiggins, KL ; Kuo, JZ ; Taylor, KD ; Hewitt, AW ; Martin, NG ; Montgomery, GW ; Sun, C ; Young, TL ; Mackey, DA ; van Zuydam, NR ; Doney, ASF ; Palmer, CNA ; Morris, AD ; Rotter, JI ; Tai, ES ; Gudnason, V ; Vingerling, JR ; Siscovick, DS ; Wang, JJ ; Wong, TY ; Wallace, GR (PUBLIC LIBRARY SCIENCE, 2013-06-12)
    Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.