Ophthalmology (Eye & Ear Hospital) - Research Publications

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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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    Retinal Vascular Fractal Dimension and Risk of Early Diabetic Retinopathy A prospective study of children and adolescents with type 1 diabetes
    Lim, SW ; Liew, G ; Cheung, N ; Islam, FMA ; Wang, JJ ; Jenkins, AJ ; Donaghue, KC ; Wong, TY (AMER DIABETES ASSOC, 2009-11)
    OBJECTIVE: To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a hospital-based prospective study of 590 patients aged 12-20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol. RESULTS: Over a mean +/- SD follow-up period of 2.9 +/- 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy. CONCLUSIONS: Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes.
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    Flicker Light-Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy
    Nguyen, TT ; Shaw, J ; Kawasaki, R ; Vilser, W ; Wang, JJ ; Wong, TY ; Kreis, AJ (AMER DIABETES ASSOC, 2009-11)
    OBJECTIVE: Flicker light-induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light-induced vasodilation in individuals with diabetes and diabetic retinopathy. RESEARCH DESIGN AND METHODS: Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light-induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs. RESULTS: Mean +/- SD age was 56.5 +/- 11.8 years for those with diabetes and 48.0 +/- 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 +/- 2.10 vs. 3.46 +/- 2.36%, P < 0.001 for arteriolar and 2.83 +/- 2.10 vs. 3.98 +/- 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light-induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5-59.1], P < 0.001 and 8.14 [3.1-21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light-induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2-4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3-4.5], P = 0.004 for venular dilation). CONCLUSIONS: Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.
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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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    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 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.
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    Genome-Wide Association Study of Retinopathy in Individuals without Diabetes
    Jensen, RA ; Sim, X ; Li, X ; Cotch, MF ; Ikram, MK ; Holliday, EG ; Eiriksdottir, G ; Harris, TB ; Jonasson, F ; Klein, BEK ; Launer, LJ ; Smith, AV ; Boerwinkle, E ; Cheung, N ; Hewitt, AW ; Liew, G ; Mitchell, P ; Wang, JJ ; Attia, J ; Scott, R ; Glazer, NL ; Lumley, T ; McKnight, B ; Psaty, BM ; Taylor, K ; Hofman, A ; de Jong, PTVM ; Rivadeneira, F ; Uitterlinden, AG ; Tay, W-T ; Teo, YY ; Seielstad, M ; Liu, J ; Cheng, C-Y ; Saw, S-M ; Aung, T ; Ganesh, SK ; O'Donnell, CJ ; Nalls, MA ; Wiggins, KL ; Kuo, JZ ; van Duijn, CM ; Gudnason, V ; Klein, R ; Siscovick, DS ; Rotter, JI ; Tai, ES ; Vingerling, J ; Wong, TY ; Mittal, B (PUBLIC LIBRARY SCIENCE, 2013-02-05)
    BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
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    Seven new loci associated with age-related macular degeneration
    Fritsche, LG ; Chen, W ; Schu, M ; Yaspan, BL ; Yu, Y ; Thorleifsson, G ; Zack, DJ ; Arakawa, S ; Cipriani, V ; Ripke, S ; Igo, RP ; Buitendijk, GHS ; Sim, X ; Weeks, DE ; Guymer, RH ; Merriam, JE ; Francis, PJ ; Hannum, G ; Agarwal, A ; Armbrecht, AM ; Audo, I ; Aung, T ; Barile, GR ; Benchaboune, M ; Bird, AC ; Bishop, PN ; Branham, KE ; Brooks, M ; Brucker, AJ ; Cade, WH ; Cain, MS ; Campochiaroll, PA ; Chan, C-C ; Cheng, C-Y ; Chew, EY ; Chin, KA ; Chowers, I ; Clayton, DG ; Cojocaru, R ; Conley, YP ; Cornes, BK ; Daly, MJ ; Dhillon, B ; Edwards, A ; Evangelou, E ; Fagemess, J ; Ferreyra, HA ; Friedman, JS ; Geirsdottir, A ; George, RJ ; Gieger, C ; Gupta, N ; Hagstrom, SA ; Harding, SP ; Haritoglou, C ; Heckenlively, JR ; Hoz, FG ; Hughes, G ; Ioannidis, JPA ; Ishibashi, T ; Joseph, P ; Jun, G ; Kamatani, Y ; Katsanis, N ; Keilhauer, CN ; Khan, JC ; Kim, IK ; Kiyohara, Y ; Klein, BEK ; Klein, R ; Kovach, JL ; Kozak, I ; Lee, CJ ; Lee, KE ; Lichtner, P ; Lotery, AJ ; Meitinger, T ; Mitchell, P ; Mohand-Saied, S ; Moore, AT ; Morgan, DJ ; Morrison, MA ; Myers, CE ; Naj, AC ; Nakamura, Y ; Okada, Y ; Orlin, A ; Ortube, MC ; Othman, MI ; Pappas, C ; Park, KH ; Pauer, GJT ; Peachey, NS ; Poch, O ; Priya, RR ; Reynolds, R ; Richardson, AJ ; Ripp, R ; Rudolph, G ; Ryu, E ; Sahel, J-A ; Schaumberg, DA ; Scholl, HPN ; Schwartz, SG ; Scott, WK ; Shahid, H ; Sigurdsson, H ; Silvestri, G ; Sivakumaran, TA ; Smith, RT ; Sobrin, L ; Souied, EH ; Stambolian, DE ; Stefansson, H ; Sturgill-Short, GM ; Takahashi, A ; Tosakulwong, N ; Truitt, BJ ; Tsironi, EE ; Uitterlinden, AG ; van Duijn, CM ; Vijaya, L ; Vingerling, JR ; Vithana, EN ; Webster, AR ; Wichmann, H-E ; Winkler, TW ; Wong, TY ; Wright, AF ; Zelenika, D ; Zhang, M ; Zhao, L ; Zhang, K ; Klein, ML ; Hageman, GS ; Lathrop, GM ; Stefansson, K ; Allikmets, R ; Baird, PN ; Gorin, MB ; Wang, JJ ; Klaver, CCW ; Seddon, JM ; Pericak-Vance, MA ; Iyengar, SK ; Yates, JRW ; Swaroop, A ; Weber, BHF ; Kubo, M ; DeAngelis, MM ; Leveillard, T ; Thorsteinsdottir, U ; Haines, JL ; Farrer, LA ; Heid, IM ; Abecasis, GR (NATURE PORTFOLIO, 2013-04)
    Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.