26 results on '"Shah, Rupal L."'
Search Results
2. Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci
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Shah, Rupal L. and Guggenheim, Jeremy A.
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- 2018
- Full Text
- View/download PDF
3. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error
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Tedja, Milly S., Wojciechowski, Robert, Hysi, Pirro G., Eriksson, Nicholas, Furlotte, Nicholas A., Verhoeven, Virginie J. M., Iglesias, Adriana I., Meester-Smoor, Magda A., Tompson, Stuart W., Fan, Qiao, Khawaja, Anthony P., Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B., Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Paterson, Andrew D., Hosseini, S. Mohsen, Shah, Rupal L., Williams, Cathy, Teo, Yik Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E., Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F., The CREAM Consortium, 23andMe Research Team, UK Biobank Eye and Vision Consortium, Joshi, Peter K., Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N., Zeller, Tanja, van der Spek, Peter J., Haak, Roxanna, Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M., Iyengar, Sudha K., Lass, Jonathan H., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Vingerling, Johannes R., Lehtimäki, Terho, Raitakari, Olli T., Biino, Ginevra, Concas, Maria Pina, Schwantes-An, Tae-Hwi, Igo, Jr, Robert P., Cuellar-Partida, Gabriel, Martin, Nicholas G., Craig, Jamie E., Gharahkhani, Puya, Williams, Katie M., Nag, Abhishek, Rahi, Jugnoo S., Cumberland, Phillippa M., Delcourt, Cécile, Bellenguez, Céline, Ried, Janina S., Bergen, Arthur A., Meitinger, Thomas, Gieger, Christian, Wong, Tien Yin, Hewitt, Alex W., Mackey, David A., Simpson, Claire L., Pfeiffer, Norbert, Pärssinen, Olavi, Baird, Paul N., Vitart, Veronique, Amin, Najaf, van Duijn, Cornelia M., Bailey-Wilson, Joan E., Young, Terri L., Saw, Seang-Mei, Stambolian, Dwight, MacGregor, Stuart, Guggenheim, Jeremy A., Tung, Joyce Y., Hammond, Christopher J., and Klaver, Caroline C. W.
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- 2018
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4. Time Spent Outdoors Partly Accounts for the Effect of Education on Myopia
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Clark, Rosie, Kneepkens, Sander C.M., Plotnikov, Denis, Shah, Rupal L., Huang, Yu, L. Tideman, J. Willem, Klaver, Caroline C.W., Atan, Denize, Williams, Cathy, Guggenheim, Jeremy A., Clark, Rosie, Kneepkens, Sander C.M., Plotnikov, Denis, Shah, Rupal L., Huang, Yu, L. Tideman, J. Willem, Klaver, Caroline C.W., Atan, Denize, Williams, Cathy, and Guggenheim, Jeremy A.
- Abstract
PURPOSE:The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing. METHODS:This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parents and Children, and Generation R. Genetic variants associated with years spent in education or time spent outdoors were used as instrumental variables. The main outcome measures were: (1) spherical equivalent refractive error attained by adulthood, and (2) risk of an early age-of-onset of spectacle wear (EAOSW), defined as an age-of-onset of 15 years or below. RESULTS:Time spent outdoors was found to have a small genetic component (heritability 9.8%) that tracked from childhood to adulthood. A polygenic score for time outdoors was associated with children’s time outdoors; a polygenic score for years spent in education was inversely associated with children’s time outdoors. Accounting for the relationship between time spent outdoors and myopia in a multivariable Mendelian randomization analysis reduced the size of the causal effect of more years in education on myopia to −0.17 diopters (D) per additional year of formal education (95% confidence interval [CI] = −0.32 to −0.01) compared with the estimate from a univariable Mendelian randomization analysis of −0.27 D per year (95% CI = −0.41 to −0.13). Comparable results were obtained for the outcome EAOSW. CONCLUSIONS:Accounting for the effects of time outdoors reduced the estimated causal effect of education on myopia by 40%. These results suggest about half of the relationship between education and myopia may be mediated by children not being outdoors during schooling.
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- 2023
5. Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia
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Tkatchenko, Tatiana V., Shah, Rupal L., Nagasaki, Takayuki, and Tkatchenko, Andrei V.
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- 2019
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6. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
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Zheng, Ju-Sheng, Luan, Jian'an, Sofianopoulou, Eleni, Sharp, Stephen J., Day, Felix R., Imamura, Fumiaki, Gundersen, Thomas E., Lotta, Luca A., Sluijs, Ivonne, Stewart, Isobel D., Shah, Rupal L., van der Schouw, Yvonne T., Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C., Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W., Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K., Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay-Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M., Overvad, Kim, Olsen, Anja, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke M. W., Tong, Tammy Y. N., Tumino, Rosario, Tsilidis, Konstantinos K., Danesh, John, Riboli, Elio, Butterworth, Adam S., Langenberg, Claudia, Forouhi, Nita G., and Wareham, Nicholas J.
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Vitamin D deficiency -- Complications and side effects -- Physiological aspects -- Genetic aspects ,Type 2 diabetes -- Risk factors -- Development and progression -- Genetic aspects ,Biological sciences - Abstract
Background Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D.sub.3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D.sub.3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D.sub.3 (N = 40,562), and C3-epi-25(OH)D.sub.3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D.sub.3 and 3 loci associated with C3-epi-25(OH)D.sub.3 . Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D.sub.3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D.sub.3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D.sub.3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D.sub.3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Author(s): Ju-Sheng Zheng 1,2,*, Jian'an Luan 1, Eleni Sofianopoulou 3,4, Stephen J. Sharp 1, Felix R. Day 1, Fumiaki Imamura 1, Thomas E. Gundersen 5, Luca A. Lotta 1, Ivonne [...]
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- 2020
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7. Genome-wide association studies for corneal and refractive astigmatism in UK Biobank demonstrate a shared role for myopia susceptibility loci
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Shah, Rupal L, Guggenheim, Jeremy A, UK Biobank Eye And Vision Consortium, Shah, Rupal L [0000-0001-8789-8869], Guggenheim, Jeremy A [0000-0001-5164-340X], and Apollo - University of Cambridge Repository
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Male ,genetic structures ,Ubiquitin-Protein Ligases ,Astigmatism ,Nuclear Proteins ,Middle Aged ,Polymorphism, Single Nucleotide ,eye diseases ,United Kingdom ,White People ,Corneal Diseases ,Cornea ,Myopia ,Guanine Nucleotide Exchange Factors ,Humans ,Female ,Genetic Predisposition to Disease ,sense organs ,Biological Specimen Banks ,Genome-Wide Association Study - Abstract
Previous studies have suggested that naturally occurring genetic variation contributes to the risk of astigmatism. The purpose of this investigation was to identify genetic markers associated with corneal and refractive astigmatism in a large-scale European ancestry cohort (UK Biobank) who underwent keratometry and autorefraction at an assessment centre. Genome-wide association studies for corneal and refractive astigmatism were performed in individuals of European ancestry (N = 86,335 and 88,005 respectively), with the mean corneal astigmatism or refractive astigmatism in fellow eyes analysed as a quantitative trait (dependent variable). Genetic correlation between the two traits was calculated using LD Score regression. Gene-based and gene-set tests were carried out using MAGMA. Single marker-based association tests for corneal astigmatism identified four genome-wide significant loci (P < 5 × 10-8) near the genes ZC3H11B (1q41), LINC00340 (6p22.3), HERC2/OCA2 (15q13.1) and NPLOC4/TSPAN10 (17q25.3). Three of these loci also demonstrated genome-wide significant association with refractive astigmatism: LINC00340, HERC2/OCA2 and NPLOC4/TSPAN10. The genetic correlation between corneal and refractive astigmatism was 0.85 (standard error = 0.068, P = 1.37 × 10-35). Here, we have undertaken the largest genome-wide association studies for corneal and refractive astigmatism to date and identified four novel loci for corneal astigmatism, two of which were also novel loci for refractive astigmatism. These loci have previously demonstrated association with axial length (ZC3H11B), myopia (NPLOC4), spherical equivalent refractive error (LINC00340) and eye colour (HERC2). The shared role of these novel candidate genes for astigmatism lends further support to the shared genetic susceptibility of myopia and astigmatism.
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- 2018
8. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
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Cardiovasculaire Epi Team 1, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Zheng, Ju Sheng, Luan, Jian'an, Sofianopoulou, Eleni, Sharp, Stephen J., Day, Felix R., Imamura, Fumiaki, Gundersen, Thomas E., Lotta, Luca A., Sluijs, Ivonne, Stewart, Isobel D., Shah, Rupal L., Van Der Schouw, Yvonne T., Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C., Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W., Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K., Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M., Overvad, Kim, Olsen, Anja, Panico, Salvatore, Ramón Quirós, J., Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke M.W., Tong, Tammy Y.N., Tumino, Rosario, Tsilidis, Konstantinos K., Danesh, John, Riboli, Elio, Butterworth, Adam S., Langenberg, Claudia, Forouhi, Nita G., Wareham, Nicholas J., Cardiovasculaire Epi Team 1, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Zheng, Ju Sheng, Luan, Jian'an, Sofianopoulou, Eleni, Sharp, Stephen J., Day, Felix R., Imamura, Fumiaki, Gundersen, Thomas E., Lotta, Luca A., Sluijs, Ivonne, Stewart, Isobel D., Shah, Rupal L., Van Der Schouw, Yvonne T., Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C., Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W., Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K., Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M., Overvad, Kim, Olsen, Anja, Panico, Salvatore, Ramón Quirós, J., Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke M.W., Tong, Tammy Y.N., Tumino, Rosario, Tsilidis, Konstantinos K., Danesh, John, Riboli, Elio, Butterworth, Adam S., Langenberg, Claudia, Forouhi, Nita G., and Wareham, Nicholas J.
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- 2020
9. Meta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes
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Bowker, Nicholas, primary, Shah, Rupal L., additional, Sharp, Stephen J., additional, Luan, Jian'an, additional, Stewart, Isobel D., additional, Wheeler, Eleanor, additional, Ferreira, Manuel A.R., additional, Baras, Aris, additional, Wareham, Nicholas J., additional, Langenberg, Claudia, additional, and Lotta, Luca A., additional
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- 2020
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10. Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci
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Manousaki, Despoina, primary, Mitchell, Ruth, additional, Dudding, Tom, additional, Haworth, Simon, additional, Harroud, Adil, additional, Forgetta, Vincenzo, additional, Shah, Rupal L., additional, Luan, Jian’an, additional, Langenberg, Claudia, additional, Timpson, Nicholas J., additional, and Richards, J. Brent, additional
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- 2020
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11. A genome-wide association study of corneal astigmatism:The CREAM Consortium
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Shah, Rupal L, Li, Qing, Zhao, Wanting, Tedja, Milly S, Tideman, J Willem L, Khawaja, Anthony P, Fan, Qiao, Yazar, Seyhan, Williams, Katie M, Verhoeven, Virginie J M, Xie, Jing, Wang, Ya Xing, Hess, Moritz, Nickels, Stefan, Lackner, Karl J, Pärssinen, Olavi, Wedenoja, Juho, Biino, Ginevra, Concas, Maria Pina, Uitterlinden, André, Rivadeneira, Fernando, Jaddoe, Vincent W V, Hysi, Pirro G, Sim, Xueling, Tan, Nicholas, Tham, Yih-Chung, Sensaki, Sonoko, Hofman, Albert, Vingerling, Johannes R, Jonas, Jost B, Hammond, Christopher J, Höhn, René, Baird, Paul N, Wong, Tien-Yin, Cheng, Chinfsg-Yu, Teo, Yik Ying, Mackey, David A, Williams, Cathy, Saw, Seang-Mei, Klaver, Caroline C W, Guggenheim, Jeremy A, and Bailey-Wilson, Joan E
- Abstract
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 thePDGFRAgene, gene-based analysis identified three novel candidate genes,CLDN7,ACP2, andTNFAIP8L3, 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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- 2018
12. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error
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Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., Klaver, C.C.W., Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., and Klaver, C.C.W.
- Abstract
Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.
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- 2018
13. Time outdoors at specific ages during early childhood and the risk of incident myopia
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Shah, Rupal L., Huang, Yu, Guggenheim, Jeremy Andrew, Williams, Cathy, Shah, Rupal [0000-0001-8789-8869], and Apollo - University of Cambridge Repository
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Male ,Time Factors ,Adolescent ,Epidemiology ,Refraction, Ocular ,Leisure Activities ,Risk Factors ,Prevalence ,Myopia ,Humans ,refractive error ,Longitudinal Studies ,Child ,Exercise ,Clinical and Epidemiologic Research ,time outdoors ,Incidence ,Time outdoors ,Refractive error ,ALSPAC ,England ,Reading ,Child, Preschool ,RE ,epidemiology ,Female - Abstract
Purpose: Time outdoors during childhood is negatively associated with incident myopia. Consequently, additional time outdoors has been suggested as a public health intervention to reduce the prevalence of myopia. We investigated whether there were specific ages during early childhood when the time outdoors versus incident myopia association was strongest.Methods: Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied from age 2 to 15 years. Parentally reported time outdoors and time spent reading were assessed longitudinally in early childhood (ages 2, 3, 4, 5, 7, and 9 years). Noncycloplegic autorefraction was carried out longitudinally in later childhood (ages 10, 11, 12, and 15 years). Information was available for 2833 participants. Cox proportional hazards regression was used to test for association between time outdoors and incident myopia.Results: From 3 years of age onward, greater time outdoors was associated with a reduced risk of incident myopia. The hazard ratio for myopia changed progressively from 0.90 (95% CI 0.83-0.98, P = 0.012) at age 3 years, to 0.86 (95% CI 0.78-0.93, P = 0.001) at age 9 years, for each additional SD of time spent outdoors per day. These associations were independent of two major risk factors for myopia: time reading and number of myopic parents.Conclusions: Additional time spent outdoors across the 3 to 9 years age range was associated with a reduced incidence of myopia between ages 10 and 15 years. There was a trend for the association to increase toward the older end of the 3 to 9 years range.
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- 2017
14. Time Outdoors at Specific Ages During Early Childhood and the Risk of Incident Myopia
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Shah, Rupal L., primary, Huang, Yu, additional, Guggenheim, Jeremy A., additional, and Williams, Cathy, additional
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- 2017
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15. Abstracts from the 15th International Myopia Conference
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Benavente-Perez, Alexandra, primary, Nour, Ann, additional, Ansel, Tobin, additional, Abarr, Kathleen, additional, Yan, Luying, additional, Roden, Keisha, additional, Troilo, David, additional, Lu, Chanyi, additional, Pan, Miaozhen, additional, Zheng, Min, additional, Qu, Jia, additional, Zhou, Xiangtian, additional, Wildsoet, Christine F., additional, Lu, Fan, additional, Chen, Jie, additional, Bao, Jinhua, additional, Hu, Liang, additional, Wang, Qinmei, additional, Jin, Zibing, additional, Rucker, Frances, additional, Britton, Stephanie, additional, Hanowsky, Stephan, additional, Spatcher, Molly, additional, Kuo, Hui-Ying, additional, Ke, Ching-Hsiu, additional, Kuo, I-Hsin, additional, Peng, Chien-Chun, additional, Sun, Han-Yin, additional, Morgan, Ian G., additional, Guggenheim, Jeremy A., additional, Shah, Rupal L., additional, Williams, Cathy, additional, Yang, Jinglei, additional, Reinach, Peter S., additional, Zhang, Sen, additional, Sun, Wenfeng, additional, Liu, Bo, additional, Li, Fen, additional, Li, Xiaoqing, additional, Zhao, Aihua, additional, Chen, Tianlu, additional, Jia, Wei, additional, Jiang, Jun, additional, Wu, Haoran, additional, Tsubota, Kazuo, additional, Ozawa, Hiroko, additional, Torii, Hidemasa, additional, Takamizawa, Shigemasa, additional, Kurihara, Toshihide, additional, Negishi, Kazuno, additional, Graef, Klaus, additional, Rathbun, Daniel, additional, Schaeffel, Frank, additional, Ghodsi, Ladan, additional, Stell, William K., additional, Pardue, Machelle T., additional, Chakraborty, Ranjay, additional, Park, Han na, additional, Sidhu, Curran S., additional, Iuvone, P. Michael, additional, Collins, Michael J, additional, Srinvasalu, Nethrajeith, additional, McFadden, Sally A., additional, Baird, Paul N., additional, Artal, Pablo, additional, Cho, Pauline, additional, Cheung, SW, additional, Wu, Pei-Chang, additional, Hoang, Quan V., additional, Lee, Duk C., additional, Landis, Erica G., additional, Bergen, Michael A., additional, Sidhu, Curran, additional, Hattar, Samer, additional, Stone, Richard A., additional, Metlapally, Ravi, additional, Li, Ruiqin, additional, Xu, Qinglin, additional, Zhong, Hong, additional, Pan, Chenglin, additional, Lan, Weizhong, additional, Li, Xiaoning, additional, Chen, Ling, additional, Yang, Zhikuan, additional, Read, Scott A., additional, Saw, Seang-Mei, additional, Weng, Shi-Jun, additional, Wu, Xiao-Hua, additional, Qian, Kang-Wei, additional, Li, Yun-Yun, additional, Xu, Guo-Zhong, additional, Huang, Furong, additional, Yang, Xiong-Li, additional, Zhong, Yong-Mei, additional, Smith, Earl L, additional, Arumugam, Baskar, additional, Hung, Li-Fang, additional, Ostrin, Lisa A., additional, Trier, Klaus, additional, Jong, Monica, additional, Holden, Brien A., additional, Lam, Thomas Chuen, additional, Shan, Samantha, additional, Zuo, Bing, additional, Tse, Dennis Yan-yin, additional, Bian, Jingfang, additional, Li, King-Kit, additional, Liu, Quan, additional, To, Chi-ho, additional, Gawne, Timothy J., additional, Siegwart, John T., additional, Ward, Alexander H., additional, Norton, Thomas T., additional, Zhang, Yan, additional, Liu, Yue, additional, Ho, Carol, additional, Phan, Eileen, additional, Hang, Abraham, additional, Eng, Emily, additional, and Wildsoet, Christine, additional
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- 2016
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- View/download PDF
16. A genome-wide association study of corneal astigmatism: The CREAM Consortium.
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Shah, Rupal L., Qing Li, Wanting Zhao, Tedja, Milly S., Tideman, J. Willem L., Khawaja, Anthony P., Qiao Fan, Yazar, Seyhan, Williams, Katie M., Verhoeven, Virginie J. M., Jing Xie, Ya Xing Wang, Hess, Moritz, Nickels, Stefan, Lackner, Karl J., Pärssinen, Olavi, Wedenoja, Juho, Biino, Ginevra, Concas, Maria Pina, and Uitterlinden, André
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- 2018
17. A genome-wide association study of corneal astigmatism
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Shah, Rupal L., Qing Li, Wanting Zhao, Tedja, Milly S., Tideman, J. Willem L., Khawaja, Anthony P., Qiao Fan, Seyhan Yazar, Williams, Katie M., Verhoeven, Virginie J. M., Jing Xie, Ya Xing Wang, Moritz Hess, Stefan Nickels, Lackner, Karl J., Olavi Pärssinen, Juho Wedenoja, Ginevra Biino, Maria Pina Concas, André Uitterlinden, Fernando Rivadeneira, Jaddoe, Vincent W. V., Hysi, Pirro G., Xueling Sim, Nicholas Tan, Yih-Chung Tham, Sonoko Sensaki, Albert Hofman, Vingerling, Johannes R., Jonas, Jost B., Hammond, Christopher J., René Höhn, Baird, Paul N., Tien-Yin Wong, Chinfsg-Yu Cheng, Yik Ying Teo, Mackey, David A., Cathy Williams, Seang-Mei Saw, Klaver, Caroline C. W., Guggenheim, Jeremy A., Bailey-Wilson, Joan E., and Cream, The Consortium
18. A genome-wide association study of corneal astigmatism: The CREAM Consortium
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Shah, Rupal L., Li, Qing, Zhao, Wanting, Tedja, Milly S., Tideman, J. Willem L., Khawaja, Anthony P., Fan, Qiao, Yazar, Seyhan, Williams, Katie M., Verhoeven, Virginie J. M., Xie, Jing, Wang, Ya Xing, Hess, Moritz, Nickels, Stefan, Lackner, Karl J., Parssinen, Olavi, Wedenoja, Juho, Biino, Ginevra, Concas, Maria Pina, Uitterlinden, Andre, Rivadeneira, Fernando, Jaddoe, Vincent W. V., Hysi, Pirro G., Sim, Xueling, Tan, Nicholas, Tham, Yih-Chung, Sensaki, Sonoko, Hofman, Albert, Vingerling, Johannes R., Jonas, Jost B., Mitchell, Paul, Hammond, Christopher J., Hoehn, Rene, Baird, Paul N., Tien Y Wong, Cheng, Chinfsg-Yu, Teo, Yik Ying, Mackey, David A., Williams, Cathy, Saw, Seang-Mei, Klaver, Caroline C. W., Guggenheim, Jeremy A., Bailey-Wilson, Joan E., Epidemiology, Ophthalmology, Internal Medicine, and Pediatrics
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0301 basic medicine ,Receptor, Platelet-Derived Growth Factor alpha ,Acid Phosphatase ,Gene Expression ,610 Medicine & health ,biomarkkerit ,Polymorphism, Single Nucleotide ,White People ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Corneal Diseases ,Cohort Studies ,Cornea ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Odds Ratio ,Humans ,Genetic Predisposition to Disease ,sarveiskalvo ,geenit ,Intracellular Signaling Peptides and Proteins ,Astigmatism ,030104 developmental biology ,silmätaudit ,Claudins ,genetic markers ,030221 ophthalmology & optometry ,corneal astigmatism ,Software ,silmät ,Research Article ,Genome-Wide Association Study - Abstract
Contains fulltext : 191261.pdf (Publisher’s version ) (Open Access) 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=5.55x10(-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.
19. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
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Zheng, Ju-Sheng, Luan, Jian’an, Sofianopoulou, Eleni, Sharp, Stephen J., Day, Felix R., Imamura, Fumiaki, Gundersen, Thomas E., Lotta, Luca A., Sluijs, Ivonne, Stewart, Isobel D., Shah, Rupal L., Van Der Schouw, Yvonne T., Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C., Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W., Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K., Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay-Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M., Overvad, Kim, Olsen, Anja, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke M. W., Tong, Tammy Y. N., Tumino, Rosario, Tsilidis, Konstantinos K., Danesh, John, Riboli, Elio, Butterworth, Adam S., Langenberg, Claudia, Forouhi, Nita G., and Wareham, Nicholas J.
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Medicine and health sciences ,Physical sciences ,Research and analysis methods ,Biology and life sciences ,FOS: Physical sciences ,3. Good health ,Research Article - Abstract
Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014, Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.
20. A genome-wide association study of corneal astigmatism
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Cream, Consortium, Shah, Rupal L., Qing Li, Wanting Zhao, Tedja, Milly S., Tideman, J. Willem L., Khawaja, Anthony P., Qiao Fan, Seyhan Yazar, Williams, Katie M., Verhoeven, Virginie J. M., Jing Xie, Ya Xing Wang, Moritz Hess, Stefan Nickels, Lackner, Karl J., Olavi Parssinen, Juho Wedenoja, Ginevra Biino, Maria Pina Concas, Andre Uitterlinden, Fernando Rivadeneira, Jaddoe, Vincent W. V., Hysi, Pirro G., Xueling Sim, Nicholas Tan, Yih-Chung Tham, Sonoko Sensaki, Albert Hofman, Vingerling, Johannes R., Jonas, Jost B., Paul Mitchell, Hammond, Christopher J., Rene Hoehn, Baird, Paul N., Tien-Yin Wong, Chinfsg-Yu Cheng, Yik Ying Teo, Mackey, David A., Cathy Williams, Seang-Mei Saw, Klaver, Caroline C. W., Guggenheim, Jeremy A., and Bailey-Wilson, Joan E.
21. A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus
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Plotnikov, Denis, Shah, Rupal L, Rodrigues, Jamille N, Cumberland, Phillippa M, Rahi, Jugnoo S, Hysi, Pirro G, Atan, Denize, Williams, Cathy, Guggenheim, Jeremy A, and UK Biobank Eye And Vision Consortium
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Adult ,Male ,genetic structures ,Tetraspanins ,Visual Acuity ,Polymorphism, Single Nucleotide ,Retina ,Cohort Studies ,Mice ,Risk Factors ,Animals ,Humans ,10. No inequality ,Child ,Aged ,Cyclic Nucleotide Phosphodiesterases, Type 6 ,Nuclear Proteins ,Middle Aged ,eye diseases ,3. Good health ,Strabismus ,Case-Control Studies ,Multigene Family ,Mutation ,Female ,Genome-Wide Association Study - Abstract
Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus.
22. Time Outdoors at Specific Ages During Early Childhood and the Risk of Incident Myopia
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Shah, Rupal L, Huang, Yu, Guggenheim, Jeremy A, and Williams, Cathy
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Male ,Time Factors ,Adolescent ,Incidence ,Refraction, Ocular ,3. Good health ,Leisure Activities ,England ,Reading ,Risk Factors ,Child, Preschool ,Myopia ,Prevalence ,Humans ,Female ,Longitudinal Studies ,Child ,Exercise - Abstract
PURPOSE: Time outdoors during childhood is negatively associated with incident myopia. Consequently, additional time outdoors has been suggested as a public health intervention to reduce the prevalence of myopia. We investigated whether there were specific ages during early childhood when the time outdoors versus incident myopia association was strongest. METHODS: Children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied from age 2 to 15 years. Parentally reported time outdoors and time spent reading were assessed longitudinally in early childhood (ages 2, 3, 4, 5, 7, and 9 years). Noncycloplegic autorefraction was carried out longitudinally in later childhood (ages 10, 11, 12, and 15 years). Information was available for 2833 participants. Cox proportional hazards regression was used to test for association between time outdoors and incident myopia. RESULTS: From 3 years of age onward, greater time outdoors was associated with a reduced risk of incident myopia. The hazard ratio for myopia changed progressively from 0.90 (95% CI 0.83-0.98, P = 0.012) at age 3 years, to 0.86 (95% CI 0.78-0.93, P = 0.001) at age 9 years, for each additional SD of time spent outdoors per day. These associations were independent of two major risk factors for myopia: time reading and number of myopic parents. CONCLUSIONS: Additional time spent outdoors across the 3 to 9 years age range was associated with a reduced incidence of myopia between ages 10 and 15 years. There was a trend for the association to increase toward the older end of the 3 to 9 years range.
23. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
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Zheng, Ju-Sheng, Luan, Jian'an, Sofianopoulou, Eleni, Sharp, Stephen J, Day, Felix R, Imamura, Fumiaki, Gundersen, Thomas E, Lotta, Luca A, Sluijs, Ivonne, Stewart, Isobel D, Shah, Rupal L, Van Der Schouw, Yvonne T, Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C, Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W, Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K, Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay-Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M, Overvad, Kim, Olsen, Anja, Panico, Salvatore, Quirós, J Ramón, Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke MW, Tong, Tammy YN, Tumino, Rosario, Tsilidis, Konstantinos K, Danesh, John, Riboli, Elio, Butterworth, Adam S, Langenberg, Claudia, Forouhi, Nita G, and Wareham, Nicholas J
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Adult ,Male ,Mendelian Randomization Analysis ,Middle Aged ,White People ,3. Good health ,Diabetes Mellitus, Type 2 ,Risk Factors ,Dietary Supplements ,Humans ,Female ,Prospective Studies ,Vitamin D ,Genome-Wide Association Study - Abstract
BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.
24. Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci
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Manousaki, Despoina, Mitchell, Ruth, Dudding, Tom, Haworth, Simon, Harroud, Adil, Forgetta, Vincenzo, Shah, Rupal L, Luan, Jian'an, Langenberg, Claudia, Timpson, Nicholas J, and Richards, J Brent
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2. Zero hunger ,Male ,genome-wide association studies ,Humans ,rare variants ,partitioned heritability ,Female ,vitamin D ,genetic correlation ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study ,gene-environment interaction ,pathway analysis - Abstract
We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.
25. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis
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Nita G. Forouhi, Kim Overvad, Ivonne Sluijs, Tammy Y.N. Tong, Christina C. Dahm, Kay-Tee Khaw, Thomas E. Gundersen, José María Huerta, Peter M. Nilsson, Miguel Rodríguez-Barranco, Nasser Laouali, Adam S. Butterworth, Giovanna Masala, Sara Grioni, Rosario Tumino, Anja Olsen, Stephen J. Sharp, Salvatore Panico, J. Ramón Quirós, Yvonne T. van der Schouw, Eleanor Wheeler, Rudolf Kaaks, Alicia K Heath, Eva Ardanaz, Felix R. Day, Eleni Sofianopoulou, Konstantinos K. Tsilidis, Luca A. Lotta, Nicholas J. Wareham, Douae El-Fatouhi, Claudia Langenberg, Heiner Boeing, Guy Fagherazzi, Paula Jakszyn, Olov Rolandsson, Rupal L. Shah, Mazda Jenab, Miren Dorronsoro, Ju-Sheng Zheng, Fumiaki Imamura, Isobel D. Stewart, Elio Riboli, Paul W. Franks, Louise Hansen, John Danesh, Carlotta Sacerdote, Jian'an Luan, Niki Dimou, Annemieke M.W. Spijkerman, Tilman Kühn, Zheng, Ju-Sheng [0000-0001-6560-4890], Sharp, Stephen J [0000-0003-2375-1440], Day, Felix R [0000-0003-3789-7651], Sluijs, Ivonne [0000-0001-7758-4911], Shah, Rupal L [0000-0001-8789-8869], van der Schouw, Yvonne T [0000-0002-4605-435X], Dahm, Christina C [0000-0003-0481-2893], Dimou, Niki [0000-0003-1678-9328], Franks, Paul W [0000-0002-0520-7604], Fagherazzi, Guy [0000-0001-5033-5966], Huerta, José María [0000-0002-9637-3869], Heath, Alicia K [0000-0001-6517-1300], Hansen, Louise [0000-0002-7109-8864], Jenab, Mazda [0000-0002-0573-1852], Kühn, Tilman [0000-0001-7702-317X], Laouali, Nasser [0000-0002-8532-456X], Masala, Giovanna [0000-0002-5758-9069], Olsen, Anja [0000-0003-4788-503X], Rodríguez-Barranco, Miguel [0000-0002-9972-9779], Sacerdote, Carlotta [0000-0002-8008-5096], Tong, Tammy YN [0000-0002-0284-8959], Tumino, Rosario [0000-0003-2666-414X], Tsilidis, Konstantinos K [0000-0002-8452-8472], Riboli, Elio [0000-0001-6795-6080], Langenberg, Claudia [0000-0002-5017-7344], Forouhi, Nita G [0000-0002-5041-248X], Wareham, Nicholas J [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Sharp, Stephen J. [0000-0003-2375-1440], Day, Felix R. [0000-0003-3789-7651], Shah, Rupal L. [0000-0001-8789-8869], van der Schouw, Yvonne T. [0000-0002-4605-435X], Dahm, Christina C. [0000-0003-0481-2893], Franks, Paul W. [0000-0002-0520-7604], Heath, Alicia K. [0000-0001-6517-1300], Tong, Tammy Y. N. [0000-0002-0284-8959], Tsilidis, Konstantinos K. [0000-0002-8452-8472], Forouhi, Nita G. [0000-0002-5041-248X], and Wareham, Nicholas J. [0000-0003-1422-2993]
- Subjects
Male ,Single Nucleotide Polymorphisms ,Organic chemistry ,Genome-wide association study ,Type 2 diabetes ,VARIANTS ,030204 cardiovascular system & hematology ,Biochemistry ,Endocrinology ,Medical Conditions ,Mathematical and Statistical Techniques ,0302 clinical medicine ,DESIGN ,Risk Factors ,Medicine and Health Sciences ,Metabolites ,VITAMIN-D SUPPLEMENTATION ,030212 general & internal medicine ,Prospective Studies ,Vitamin D ,11 Medical and Health Sciences ,RISK ,Diabetis ,Statistics ,Diabetes ,Genomics ,Vitamins ,General Medicine ,Metaanalysis ,Middle Aged ,Type 2 Diabetes ,3. Good health ,European Prospective Investigation into Cancer and Nutrition ,Physical sciences ,Chemistry ,OBESITY ,Endokrinologi och diabetes ,Medicine ,LIFE-STYLE ,Female ,Life Sciences & Biomedicine ,Research Article ,Adult ,medicine.medical_specialty ,Endocrine Disorders ,DATABASE ,Vitamina D ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Endocrinology and Diabetes ,Research and Analysis Methods ,Lower risk ,White People ,Chemical compounds ,03 medical and health sciences ,Medicine, General & Internal ,General & Internal Medicine ,Internal medicine ,Organic compounds ,Diabetes Mellitus ,Genome-Wide Association Studies ,medicine ,Vitamin D and neurology ,Genetics ,Humans ,Statistical Methods ,Science & Technology ,business.industry ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Odds ratio ,Mendelian Randomization Analysis ,Genome Analysis ,medicine.disease ,Metabolism ,Diabetes Mellitus, Type 2 ,Genetic Loci ,Metabolic Disorders ,Relative risk ,Dietary Supplements ,GENETIC-DETERMINANTS ,business ,Mathematics ,Genètica ,Genome-Wide Association Study - Abstract
Background Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Using both observational and genetic analyses, Ju-Sheng Zheng and colleagues investigate the relationship between vitamin D metabolites and type 2 diabetes among European individuals., Author summary Why was this study done? There is ongoing uncertainty on whether the body’s vitamin D status indicated by blood 25-hydroxyvitamin D (25(OH)D) is relevant to the prevention of type 2 diabetes. There are conflicting findings from observational studies and a limited number of randomised controlled trials. Prior research did not distinguish between different metabolites of total 25(OH)D, including 25(OH)D3 and C3-epi-25(OH)D3, an isomer of 25(OH)D3. It is not clear whether the associations of 25(OH)D metabolites with type 2 diabetes are causal, with conflicting findings from prior Mendelian randomisation studies of total 25(OH)D and no previous Mendelian randomisation studies appraising 25(OH)D metabolites. What did the researchers do and find? The current research compared observational estimates of the association between 25(OH)D metabolites and incident type 2 diabetes with Mendelian randomisation estimates based on genetic instruments. Using multiple data sources, we performed genome-wide association studies among 120,618 individuals for total 25(OH)D, and among 40,562 individuals for the other vitamin D metabolites. Among participants of European descent, 10 genetic loci were identified for total 25(OH)D, 7 loci for 25(OH)D3 and 3 loci for C3-epi-25(OH)D3. In meta-analysis of observational studies, we found that each 1–standard deviation higher level of total 25(OH)D was associated with 20% lower risk of type 2 diabetes. The result was similar for 25(OH)D3, but for C3-epi-25(OH)D3, a positive association with type 2 diabetes was found. With up to 80,983 type 2 diabetes cases and 842,909 controls, we assessed the association of genetically predicted differences in total 25(OH)D and its metabolites with type 2 diabetes. Neither genetically predicted higher total 25(OH)D level nor genetically predicted higher levels of 25(OH)D metabolites were significantly associated with type 2 diabetes. What do these findings mean? There were conflicting findings for a link with type 2 diabetes for the observational analysis of biochemically measured 25(OH)D metabolites versus the genetically predicted levels of these metabolites. The null findings based on Mendelian randomisation analysis indicate that blood levels of 25(OH)D or its metabolites are not likely to be causal factors for the development of type 2 diabetes. The current findings together with other evidence from randomised controlled trials do not support the use of vitamin D supplementation for the prevention of type 2 diabetes.
- Published
- 2020
26. Time Spent Outdoors Partly Accounts for the Effect of Education on Myopia.
- Author
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Clark R, Kneepkens SCM, Plotnikov D, Shah RL, Huang Y, Tideman JWL, Klaver CCW, Atan D, Williams C, and Guggenheim JA
- Subjects
- Adolescent, Child, Humans, Young Adult, Educational Status, Longitudinal Studies, Risk Factors, Mendelian Randomization Analysis, Leisure Activities, Myopia epidemiology, Myopia genetics
- Abstract
Purpose: The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing., Methods: This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parents and Children, and Generation R. Genetic variants associated with years spent in education or time spent outdoors were used as instrumental variables. The main outcome measures were: (1) spherical equivalent refractive error attained by adulthood, and (2) risk of an early age-of-onset of spectacle wear (EAOSW), defined as an age-of-onset of 15 years or below., Results: Time spent outdoors was found to have a small genetic component (heritability 9.8%) that tracked from childhood to adulthood. A polygenic score for time outdoors was associated with children's time outdoors; a polygenic score for years spent in education was inversely associated with children's time outdoors. Accounting for the relationship between time spent outdoors and myopia in a multivariable Mendelian randomization analysis reduced the size of the causal effect of more years in education on myopia to -0.17 diopters (D) per additional year of formal education (95% confidence interval [CI] = -0.32 to -0.01) compared with the estimate from a univariable Mendelian randomization analysis of -0.27 D per year (95% CI = -0.41 to -0.13). Comparable results were obtained for the outcome EAOSW., Conclusions: Accounting for the effects of time outdoors reduced the estimated causal effect of education on myopia by 40%. These results suggest about half of the relationship between education and myopia may be mediated by children not being outdoors during schooling.
- Published
- 2023
- Full Text
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