Centre for Eye Research Australia (CERA) - Research Publications

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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, 2018-01-01)
    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, 2018-05-01)
    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, 2012-09-01)
    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, 2016-02-01)
    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, 2015-02-01)
    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.
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    Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4
    Ma, RCW ; Hu, C ; Tam, CH ; Zhang, R ; Kwan, P ; Leung, TF ; Thomas, GN ; Go, MJ ; Hara, K ; Sim, X ; Ho, JSK ; Wang, C ; Li, H ; Lu, L ; Wang, Y ; Li, JW ; Wang, Y ; Lam, VKL ; Wang, J ; Yu, W ; Kim, YJ ; Ng, DP ; Fujita, H ; Panoutsopoulou, K ; Day-Williams, AG ; Lee, HM ; Ng, ACW ; Fang, Y-J ; Kong, APS ; Jiang, F ; Ma, X ; Hou, X ; Tang, S ; Lu, J ; Yamauchi, T ; Tsui, SKW ; Woo, J ; Leung, PC ; Zhang, X ; Tang, NLS ; Sy, HY ; Liu, J ; Wong, TY ; Lee, JY ; Maeda, S ; Xu, G ; Cherny, SS ; Chan, TF ; Ng, MCY ; Xiang, K ; Morris, AP ; Keildson, S ; Hu, R ; Ji, L ; Lin, X ; Cho, YS ; Kadowaki, T ; Tai, ES ; Zeggini, E ; McCarthy, MI ; Hon, KL ; Baum, L ; Tomlinson, B ; So, WY ; Bao, Y ; Chan, JCN ; Jia, W (SPRINGER, 2013-06-01)
    AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
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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 PUBLISHING GROUP, 2013-04-01)
    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.