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1. Hypothesis-independent pathway analysis implicates GABA and Acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma

Author: Bailey, JNC, Yaspan, BL, Pasquale, LR, Hauser, MA, Kang, JH, Loomis, SJ, Brilliant, M, Budenz, DL, Christen, WG, Fingert, J, Gaasterland, D, Gaasterland, T, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, McCarty, CA, Moroi, SE, Richards, JE, Realini, T, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Wollstein, G, Zack, DJ, Zhang, K, Pericak-Vance, MA, Allingham, RR, Weinreb, RN, Haines, JL, and Wiggs, JL
Subjects: Genetics & Heredity, Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p
Published: 2014

2. Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma

Author: Kang, JH, Loomis, SJ, Yaspan, BL, Bailey, JC, Weinreb, RN, Lee, RK, Lichter, PR, Budenz, DL, Liu, Y, Realini, T, Gaasterland, D, Gaasterland, T, Friedman, DS, McCarty, CA, Moroi, SE, Olson, L, Schuman, JS, Singh, K, Vollrath, D, Wollstein, G, Zack, DJ, Brilliant, M, Sit, AJ, Christen, WG, Fingert, J, Forman, JP, Buys, ES, Kraft, P, Zhang, K, Allingham, RR, Pericak-Vance, MA, Richards, JE, Hauser, MA, Haines, JL, Wiggs, JL, and Pasquale, LR
Subjects: Biomedical and Clinical Sciences, Ophthalmology and Optometry, Aging, Neurosciences, Genetics, Eye Disease and Disorders of Vision, Neurodegenerative, Clinical Research, Cardiovascular, AMP-Activated Protein Kinases, Aged, Case-Control Studies, Caveolin 1, Dynamin II, Dynamins, Endothelium, Vascular, Female, GTP-Binding Proteins, Genetic Predisposition to Disease, Genotype, Glaucoma, Open-Angle, Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Intraocular Pressure, Male, Middle Aged, Muscle, Smooth, Vascular, Nitric Oxide Synthase Type III, Polymorphism, Single Nucleotide, Receptor, Endothelin B, Receptors, Endothelin, Signal Transduction, Clinical Sciences, Immunology, Opthalmology and Optometry, Ophthalmology & Optometry, Ophthalmology and optometry
Abstract: AimsVascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG.MethodsWe used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG.ResultsThe vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P
Published: 2014

3. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs

Author: Okazaki, Y., Furuno, M., Kasukawa, T., Adachi, J., Bono, H., Kondo, S., Nikaido, I., Osato, N., Saito, R., Suzuki, H., Yamanaka, I., Kiyosawa, H., Yagi, K., Tomaru, Y., Hasegawa, Y., Nogami, A., Schonbach, C., Gojobori, T., Baldarelli, R., Hill, D. P., Bult, C., Hume, D. A., Quackenbush, J., Schriml, L. M., Kanapin, A., Matsuda, H., Batalov, S., Beisel, K. W., Blake, J. A., Bradt, D., Brusic, V., Chothia, C., Corbani, L. E., Cousins, S., Dalla, E., Dragani, T. A., Fletcher, C. F., Forrest, A., Frazer, K. S., Gaasterland, T., Gariboldi, M., Gissi, C., Godzik, A., Gough, J., Grimmond, S., Gustincich, S., Hirokawa, N., Jackson, I. J., Jarvis, E. D., Kanai, A., Kawaji, H., Kawasawa, Y., Kedzierski, R. M., King, B. L., Konagaya, A., Kurochkin, I. V., Lee, Y., Lenhard, B., Lyons, P. A., Maglott, D. R., Maltais, L., Marchionni, L., McKenzie, L., Miki, H., Nagashima, T., Numata, K., Okido, T., Pavan, W. J., Pertea, G., Pesole, G., Petrovsky, N., Pillai, R., Pontius, J. U., Qi, D., Ramachandran, S., Ravasi, T., Reed, J. C., Reed, D. J., Reid, J., Ring, B. Z., Ringwald, M., Sandelin, A., Schneider, C., Semple, C. A. M., Setou, M., Shimada, K., Sultana, R., Takenaka, Y., Taylor, M. S., Teasdale, R. D., Tomita, M., Verardo, R., Wagner, L., Wahlestedt, C., Wang, Y., Watanabe, Y., Wells, C., Wilming, L. G., Wynshaw-Boris, A., Yanagisawa, M., Yang, I., Yang, L., Yuan, Z., Zavolan, M., Zhu, Y., Zimmer, A., Carninci, P., Hayatsu, N., Hirozane-Kishikawa, T., Konno, H., Nakamura, M., Sakazume, N., Sato, K., Shiraki, T., Waki, K., Kawai, J., Aizawa, K., Arakawa, T., Fukuda, S., Hara, A., Hashizume, W., Imotani, K., Ishii, Y., Itoh, M., Kagawa, I., Miyazaki, A., Sakai, K., Sasaki, D., Shibata, K., Shinagawa, A., Yasunishi, A., Yoshino, M., Waterston, R., Lander, E. S., Rogers, J., Birney, E., and Hayashizaki, Y.
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): The FANTOM Consortium and the RIKEN Genome Exploration Research Group Phase I & II Team*; FANTOM Consortium:; Y. Okazaki [1, 2]; M. Furuno [1]; T. Kasukawa [1, 3]; J. [...]
Published: 2002
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4. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC
Subjects: Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
Published: 2019

5. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author: Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), Duijn, C.M. (Cornelia) van, Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), and Duijn, C.M. (Cornelia) van
Abstract: A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
Published: 2019
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6. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author: Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, van Duijn, CM, Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, and van Duijn, CM
Abstract: A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
Published: 2019

7. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

8. Organizational characteristics and information content of an archaeal genome: 156 kb of sequence from Sulfolobus solfataricus P2

Author: Sensen, C. W., Klenk, H.-P., Singh, R. K., Allard, G., Chan, C. C.-Y., Liu, Q. Y., Penny, S. L., Young, F., Schenk, M. E., Gaasterland, T., Doolittle, W. F., Ragan, M. A., and Charlebois, R. L.
Published: 1996

9. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Author: King, R. (Richard), Struebing, F.L., Li, Y. (Yuwen), Wang, J., Koch, A.A., Bailey, JNC, Gharahkhani, P, Macgregor, S., Allingham, R.R. (R Rand), Hauser, M.A. (Michael), Wiggs, J.L. (Janey), Geisert, E.E., Allingham, R., Brilliant, M., Budenz, D., Bailey, J.C., Fingert, J., Gaasterland, D., Gaasterland, T., Haines, J.L. (Jonathan), Hark, L., Hauser, M., Igo, R., Kang, J.H. (Jae), Kraft, P. (Peter), Lee, R. (R.) van der, Lichter, P. (Peter), Liu, Y. (Yu), Moroi, S., Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A., Rhee, D., Richards, J. (John), Ritch, R., Schuman, J., Scott, W.K. (William), Singh, K, Sit, A., Vollrath, D., Weinreb, RN, Wollstein, G., Zack, D., Aung, T. (Tin), Burdon, K.P. (Kathryn), Cheng, C-Y. (Ching-Yu), Bailey, J.N.C., Craig, J.E. (Jamie), Cree, A.J. (Angela), Hammond, C.J. (Christopher), Hewit, A.W. (Alex), Höhn, R., Hysi, P.G. (Pirro), Gonzalez, A.I., Jonas, J., Khawaja, A, Khor, C.C., Klaver, C.C.W. (Caroline), Pasutto, F. (Francesca), Mackey, D., Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C., Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Duijn, C.M., Viswanathan, A. (Anand), Vitart, V. (Veronique), Wojciechowski, R. (Robert), Wong, T., Young, T.L. (Terri), Zeller, T. (Tanja), King, R. (Richard), Struebing, F.L., Li, Y. (Yuwen), Wang, J., Koch, A.A., Bailey, JNC, Gharahkhani, P, Macgregor, S., Allingham, R.R. (R Rand), Hauser, M.A. (Michael), Wiggs, J.L. (Janey), Geisert, E.E., Allingham, R., Brilliant, M., Budenz, D., Bailey, J.C., Fingert, J., Gaasterland, D., Gaasterland, T., Haines, J.L. (Jonathan), Hark, L., Hauser, M., Igo, R., Kang, J.H. (Jae), Kraft, P. (Peter), Lee, R. (R.) van der, Lichter, P. (Peter), Liu, Y. (Yu), Moroi, S., Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A., Rhee, D., Richards, J. (John), Ritch, R., Schuman, J., Scott, W.K. (William), Singh, K, Sit, A., Vollrath, D., Weinreb, RN, Wollstein, G., Zack, D., Aung, T. (Tin), Burdon, K.P. (Kathryn), Cheng, C-Y. (Ching-Yu), Bailey, J.N.C., Craig, J.E. (Jamie), Cree, A.J. (Angela), Hammond, C.J. (Christopher), Hewit, A.W. (Alex), Höhn, R., Hysi, P.G. (Pirro), Gonzalez, A.I., Jonas, J., Khawaja, A, Khor, C.C., Klaver, C.C.W. (Caroline), Pasutto, F. (Francesca), Mackey, D., Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C., Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Duijn, C.M., Viswanathan, A. (Anand), Vitart, V. (Veronique), Wojciechowski, R. (Robert), Wong, T., Young, T.L. (Terri), and Zeller, T. (Tanja)
Abstract: 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 rs7631
Published: 2018
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10. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, MacGregor, S. (Stuart), Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, and MacGregor, S. (Stuart)
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018
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11. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: analysis in Two Large Datasets

Author: Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, Pasquale, LR, Bailey, JNC, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, and Pasquale, LR
Abstract: PURPOSE: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. METHODS: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). RESULTS: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. CONCLUSIONS: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
Published: 2018

12. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis

Author: Aschard, H., Kang, J.H., Iglesias, A.I., Hysi, P., Bailey, J.N., Khawaja, A.P., Allingham, R.R., Ashley-Koch, A., Lee, R.K., Moroi, S.E., Brilliant, M.H., Wollstein, G., Schuman, J.S., Fingert, J.H., Budenz, D.L., Realini, T., Gaasterland, T., Scott, W.K., Singh, K., Sit, A.J., Igo, R.P., Jr., Song, Y.E., Hark, L., Ritch, R., Rhee, D.J., Gulati, V., Haven, S., Vollrath, D., Zack, D.J., Medeiros, F., Weinreb, R.N., Cheng, C.Y., Chasman, D.I., Christen, W.G., Pericak-Vance, M.A., Liu, Y., Kraft, P., Richards, J.E., Rosner, B.A., Hauser, M.A., Klaver, C.C.W., vanDuijn, C.M., Haines, J., Wiggs, J.L., Pasquale, L.R., Aschard, H., Kang, J.H., Iglesias, A.I., Hysi, P., Bailey, J.N., Khawaja, A.P., Allingham, R.R., Ashley-Koch, A., Lee, R.K., Moroi, S.E., Brilliant, M.H., Wollstein, G., Schuman, J.S., Fingert, J.H., Budenz, D.L., Realini, T., Gaasterland, T., Scott, W.K., Singh, K., Sit, A.J., Igo, R.P., Jr., Song, Y.E., Hark, L., Ritch, R., Rhee, D.J., Gulati, V., Haven, S., Vollrath, D., Zack, D.J., Medeiros, F., Weinreb, R.N., Cheng, C.Y., Chasman, D.I., Christen, W.G., Pericak-Vance, M.A., Liu, Y., Kraft, P., Richards, J.E., Rosner, B.A., Hauser, M.A., Klaver, C.C.W., vanDuijn, C.M., Haines, J., Wiggs, J.L., and Pasquale, L.R.
Abstract: Item does not contain fulltext, Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 x 10(-27)) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 x 10(-5)); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Published: 2017

13. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Author: Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), Jablonski, M.M. (Monica M.), Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), and Jablonski, M.M. (Monica M.)
Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with know
Published: 2017
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14. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author: 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, CY, 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, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR
Subjects: ANZRAG Consortium
Abstract: © 2016 Nature America, Inc. 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.
Published: 2016

15. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, H, Höhn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, GW, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, KS, Van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, SC, Despriet, DDG, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Van Koolwijk, LME, Rivadeneira, F, Souzeau, E, Jonsson, V, Menon, G, Mitchell, P, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Weinreb, RN, De Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Haines, JL, Kraft, P, Lee, RK, Lichter, PR, and Liu, Y
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2014 Macmillan Publishers Limited. All rights reserved. Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014

16. DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma

Author: Liu, Y., primary, Garrett, M. E., additional, Yaspan, B. L., additional, Bailey, J. C., additional, Loomis, S. J., additional, Brilliant, M., additional, Budenz, D. L., additional, Christen, W. G., additional, Fingert, J. H., additional, Gaasterland, D., additional, Gaasterland, T., additional, Kang, J. H., additional, Lee, R. K., additional, Lichter, P., additional, Moroi, S. E., additional, Realini, A., additional, Richards, J. E., additional, Schuman, J. S., additional, Scott, W. K., additional, Singh, K., additional, Sit, A. J., additional, Vollrath, D., additional, Weinreb, R., additional, Wollstein, G., additional, Zack, D. J., additional, Zhang, K., additional, Pericak-Vance, M. A., additional, Haines, J. L., additional, Pasquale, L. R., additional, Wiggs, J. L., additional, Allingham, R. R., additional, Ashley-Koch, A. E., additional, and Hauser, M. A., additional
Published: 2014
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17. Paving the future: finding suitable ISMB venues

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Rost, B., Gaasterland, T., Lengauer, T., Linial, M., Markel, S., McKay, B. J. M., Schneider, Reinhard, Horton, P., Kelso, J., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Rost, B., Gaasterland, T., Lengauer, T., Linial, M., Markel, S., McKay, B. J. M., Schneider, Reinhard, Horton, P., and Kelso, J.
Abstract: ISCB, the International Society for Computational Biology, organizes the largest event in the field of computational biology and bioinformatics, namely the annual ISMB, the international conference on Intelligent Systems for Molecular Biology. This year at ISMB 2012 in Long Beach, ISCB celebrated the 20th anniversary of its flagship meeting. ISCB is a young, lean and efficient society that aspires to make a significant impact with only limited resources. Many constraints make the choice of venues for ISMB a tough challenge. Here, we describe those challenges and invite the contribution of ideas for solutions.
Published: 2012

18. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Author: Wiggs, JL, Yaspan, BL, Hauser, MA, Kang, JH, Allingham, RR, Olson, LM, Abdrabou, W, Fan, BJ, Wang, DY, Brodeur, W, Budenz, DL, Caprioli, J, Crenshaw, A, Crooks, K, DelBono, E, Doheny, KF, Friedman, DS, Gaasterland, D, Gaasterland, T, Laurie, C, Lee, RK, Lichter, PR, Loomis, S, Liu, Y, Medeiros, FA, McCarty, C, Mirel, D, Moroi, SE, Musch, DC, Realini, A, Rozsa, FW, Schuman, JS, Scott, K, Singh, K, Stein, JD, Trager, EH, VanVeldhuisen, P, Vollrath, D, Wollstein, G, Yoneyama, S, Zhang, K, Weinreb, RN, Ernst, J, Kellis, M, Masuda, T, Zack, D, Richards, JE, Pericak-Vance, M, Pasquale, LR, Haines, JL, Wiggs, JL, Yaspan, BL, Hauser, MA, Kang, JH, Allingham, RR, Olson, LM, Abdrabou, W, Fan, BJ, Wang, DY, Brodeur, W, Budenz, DL, Caprioli, J, Crenshaw, A, Crooks, K, DelBono, E, Doheny, KF, Friedman, DS, Gaasterland, D, Gaasterland, T, Laurie, C, Lee, RK, Lichter, PR, Loomis, S, Liu, Y, Medeiros, FA, McCarty, C, Mirel, D, Moroi, SE, Musch, DC, Realini, A, Rozsa, FW, Schuman, JS, Scott, K, Singh, K, Stein, JD, Trager, EH, VanVeldhuisen, P, Vollrath, D, Wollstein, G, Yoneyama, S, Zhang, K, Weinreb, RN, Ernst, J, Kellis, M, Masuda, T, Zack, D, Richards, JE, Pericak-Vance, M, Pasquale, LR, and Haines, JL
Abstract: Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. © 2012 Wiggs et al.
Published: 2012

19. The complete genome of the crenarchaeon Sulfolobus solfataricus P2.

Author: She, Qunxin, Singh, R.K., Confalonieri, F., Zivanovic, Y., Allard, G., Awayez, Mariana J., Chan-Weiher, C.C.-Y., Clausen, Ib Groth, Curtis, B.A., De Moors, A., Erauso, G., Fletcher, C., Gordon, P.M., Heikamp-de Jong, I., Jeffries, A.C., Kozera, C.J., Medina, N., Peng, Xu, Phan, Thi Ngoc Hoa, Redder, Peter Bastue, Schenk, M.E., Theriault, C., Tolstrup, N., Charlebois, R.L., Doolittle, W.F., Duguet, M., Gaasterland, T., Garret, Roger Antony, Ragan, M.A., Sensen, C.W., Van der Oost, J., She, Qunxin, Singh, R.K., Confalonieri, F., Zivanovic, Y., Allard, G., Awayez, Mariana J., Chan-Weiher, C.C.-Y., Clausen, Ib Groth, Curtis, B.A., De Moors, A., Erauso, G., Fletcher, C., Gordon, P.M., Heikamp-de Jong, I., Jeffries, A.C., Kozera, C.J., Medina, N., Peng, Xu, Phan, Thi Ngoc Hoa, Redder, Peter Bastue, Schenk, M.E., Theriault, C., Tolstrup, N., Charlebois, R.L., Doolittle, W.F., Duguet, M., Gaasterland, T., Garret, Roger Antony, Ragan, M.A., Sensen, C.W., and Van der Oost, J.
Published: 2001

20. Enolase from Trypanosoma brucei, from the amitochondriate protist Mastigamoeba balamuthi, and from the chloroplast and cytosol of Euglena gracilis: pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway.

Author: UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - FSA/ELEC - Département d'électricité, Hannaert, Véronique, Albert, Marie-Astrid, Brinkmann, H, Nowitzki, U, Lee, Jennifer A., Sensen, C W, Gaasterland, T, Müller, M, Michels, Paulus, Martin, W., UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - FSA/ELEC - Département d'électricité, Hannaert, Véronique, Albert, Marie-Astrid, Brinkmann, H, Nowitzki, U, Lee, Jennifer A., Sensen, C W, Gaasterland, T, Müller, M, Michels, Paulus, and Martin, W.
Abstract: Genomic or cDNA clones for the glycolytic enzyme enolase were isolated from the amitochondriate pelobiont MASTIGAMOEBA: balamuthi, from the kinetoplastid TRYPANOSOMA: brucei, and from the euglenid EUGLENA: gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas EUGLENA: was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that ARABIDOPSIS: also possesses a second enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the MASTIGAMOEBA: enolase tended to branch with its homologs from TRYPANOSOMA: and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in EUGLENA: arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the EUGLENA: enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, enolases from all eukaryotes surveyed here (except EUGLENA:) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
Published: 2000

21. Gene content and organization of a 281-kbp contig from the genome of the extremely thermophilic archaeon, Sulfolobus solfataricus P2

Author: Charlebois, R.L., Singh, R.K., Chan-Weiher, C.C.-Y., Allard, G., Chow, C., Confalonieri, F., Curtis, B., Duguet, M., Erauso, G., Faguy, D., Gaasterland, T., Garrett, Roger Antony, Gordon, P., Jeffries, A.C., Kozera, C., Kushwaha, N., Lafleur, E., Medina, N., Peng, Xu, Penny, S.L., She, Qunxin, St. Jean, A., van der Oost, J., Young, F., Zivanovic, Y., Doolittle, W.F., Ragan, M.A., Sensen, C.W., Charlebois, R.L., Singh, R.K., Chan-Weiher, C.C.-Y., Allard, G., Chow, C., Confalonieri, F., Curtis, B., Duguet, M., Erauso, G., Faguy, D., Gaasterland, T., Garrett, Roger Antony, Gordon, P., Jeffries, A.C., Kozera, C., Kushwaha, N., Lafleur, E., Medina, N., Peng, Xu, Penny, S.L., She, Qunxin, St. Jean, A., van der Oost, J., Young, F., Zivanovic, Y., Doolittle, W.F., Ragan, M.A., and Sensen, C.W.
Published: 2000

22. Completing the sequence of the Sulfolobus solfataricus P2 genome

Author: Sensen, C.W., Charlebois, R.L., Chow, C., Clausen, Ib Groth, Curtis, B., Doolittle, W.F., Duguet, M., Erauso, G., Gaasterland, T., Garrett, Roger Antony, Gordon, P., Heikamp de Jong, J.I., Jeffries, A.C., Kozera, C., Medina, N., De Moors, A., van der Oost, O.J., Phan, Thi Ngoc Hien, Ragan, M., Schenk, S., She, Qunxin, Singh, R.K., Tolstrup, N., Sensen, C.W., Charlebois, R.L., Chow, C., Clausen, Ib Groth, Curtis, B., Doolittle, W.F., Duguet, M., Erauso, G., Gaasterland, T., Garrett, Roger Antony, Gordon, P., Heikamp de Jong, J.I., Jeffries, A.C., Kozera, C., Medina, N., De Moors, A., van der Oost, O.J., Phan, Thi Ngoc Hien, Ragan, M., Schenk, S., She, Qunxin, Singh, R.K., and Tolstrup, N.
Abstract: Molekylærbiologi
Published: 1998

23. Organizational characteristics and information content of an archaeal genome: 156kb of sequence from Sulfolobus solfataricus P2

Author: Sensen, C. W., primary, Klenk, H.‐P., additional, Singh, R. K., additional, Allard, G., additional, Chan, C. C.‐Y., additional, Liu, Q. Y., additional, Penny, S. L., additional, Young, F., additional, Schenk, M. E., additional, Gaasterland, T., additional, Doolittle, W. F., additional, Ragan, M. A., additional, and Charlebois, R. L., additional
Published: 1996
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24. MAGPIE/EGRET annotation of the 2.9-Mb Drosophila melanogaster Adh region

Author: Gaasterland, T, Sczyrba, A, Thomas, E, Aytekin-Kurban, G, Gordon, P, and Sensen, C W
Abstract: Our challenge in annotating the 2.91-Mb Adh region of the Drosophila melanogaster genome was to identify genetic and genomic features automatically, completely, and precisely within a 6-week period. To do so, we augmented the MAGPIE microbial genome annotation system to handle eukaryotic genomic sequence data. The new configuration required the integration of eukaryotic gene-finding tools and DNA repeat tools into the automatic data collection module. It also required us to define in MAGPIE new strategies to combine data about eukaryotic exon predictions with functional data to refine the exon predictions. At the heart of the resulting new eukaryotic genome annotation system is a reverse comparison of public protein and complementary DNA sequences against the input genome to identify missing exons and to refine exon boundaries. The software modules that add eukaryotic genome annotation capability to MAGPIE are available as EGRET (Eukaryotic Genome Rapid Evaluation Tool).
Published: 2000

25. The Sulfolobus solfataricus P2 genome project

Author: Charlebois, R. L., Gaasterland, T., Ragan, M. A., Doolittle, W. F., and Sensen, C. W.
Published: 1996
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26. Genomic insights into Mn(II) oxidation by the marine alphaproteobacterium Aurantimonas sp. strain Si85-9A1

Author: Dick, G.J., Podell, S., Johnson, H.A., Rivera-Espinoza, Y., Bernier-Latmani, R., McCarthy, J.K., Torpey, J.W., Clement, B.G., Gaasterland, T., and Tebo, B.M.

27. Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States

Author: Pasquale, L. R., Loomis, S. J., Weinreb, R. N., Kang, J. H., Yaspan, B. L., Cooke Bailey, J., Gaasterland, D., Gaasterland, T., Lee, R. K., Scott, W. K., Lichter, P. R., Budenz, D. L., Liu, Y., Realini, T., Friedman, D. S., Catherine McCarty, Moroi, S. E., Olson, L., Schuman, J. S., Singh, K., Vollrath, D., Wollstein, G., Zack, D. J., Brilliant, M., Sit, A. J., Christen, W. G., Fingert, J., Kraft, P., Zhang, K., Allingham, R. R., Pericak-Vance, M. A., Richards, J. E., Hauser, M. A., Haines, J. L., and Wiggs, J. L.
Subjects: Male, Aging, genetic structures, Neurodegenerative, Ophthalmology & Optometry, Polymorphism, Single Nucleotide, Opthalmology and Optometry, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Eye Disease and Disorders of Vision, Intraocular Pressure, Sex Characteristics, Neurosciences, Glaucoma, Estrogens, Single Nucleotide, Estrogen, eye diseases, United States, Open-Angle, Case-Control Studies, Female, sense organs, Glaucoma, Open-Angle, Metabolic Networks and Pathways, Research Article, Signal Transduction
Abstract: Purpose: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. Methods: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway-and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the metaanalyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22mmHg (high-pressure glaucoma [HPG]) or IOP 0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). Conclusions: The estrogen SNP pathway was associated with POAG among women. © 2013 Molecular Vision.

28. An open letter to the scientific journals

Author: Holstege, F., Ball, C.A., Ringwald, M., Sherlock, G., Spellman, P., Parkinson, H., Stoeckert, C.J., Rocca-Sera, P., Stewart, J.E., Brooksbank, C., Taylor, R., Causton, H.C., Cavalieri, D., Brazma, A., Quackenbush, J., Gaasterland, T., and Hingamp, P.
Published: 2002

29. Restricting query relaxation through user constraints

Author: Gaasterland, T
Published: 1993

30. Overview of selected molecular biological databases

Author: Gaasterland, T
Published: 1994
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31. Complete sequence of a 184 kb catabolic plasmid from Sphingomonas aromaticivorans strain F199.

Author: Gaasterland, T
Published: 1999

32. The Genome of the Sea Urchin Strongylocentrotus purpuratus

Author: Amro Hamdoun, Virginia Brockton, Huyen Dinh, Qiang Tu, Richard O. Hynes, Maria Ina Arnone, Wratko Hlavina, L. Courtney Smith, Mariano A. Loza, David R. Burgess, Matthew P. Hoffman, Florian Raible, Qiu Autumn Yuan, Geoffrey Okwuonu, Mark Y. Tong, Jennifer Hume, Donna Maglott, Manisha Goel, Olivier Fedrigo, Manuel L. Gonzalez-Garay, Celina E. Juliano, Judith Hernandez, Gary M. Wessel, William F. Marzluff, Audrey J. Majeske, Christian Gache, Louise Duloquin, Xingzhi Song, François Lapraz, Fowler J, Alexandre Souvorov, Jared V. Goldstone, Georgia Panopoulou, Sandra Hines, Kyle M. Judkins, Clay Davis, Christine G. Elsik, Paul Kitts, Mariano Loza-Coll, Greg Wray, Taku Hibino, Eric Röttinger, Allison M. Churcher, Annamaria Locascio, Arcady Mushegian, Masashi Kinukawa, Anna Reade, Katherine M. Buckley, I. R. Gibbons, Bert Gold, Aleksandar Milosavljevic, David Epel, Victor D. Vacquier, Ling Ling Pu, Vincenzo Cavalieri, Erin L. Allgood, Lan Zhang, Lynne V. Nazareth, Constantin N. Flytzanis, Ian Bosdet, Yi-Hsien Su, Zeev Pancer, Matthew L. Rowe, Robert C. Angerer, David R. McClay, William H. Klein, Rachel F. Gray, Julian L. Wong, Shunsuke Yaguchi, Robert Bellé, Aaron J. Mackey, Herath Jayantha Gunaratne, Karl Frederik Bergeron, Bruce P. Brandhorst, Greg Murray, Avis H. Cohen, Stephanie Bell, Kristin Tessmar-Raible, Ian K. Townley, Bertrand Cosson, Thomas D. Glenn, Jongmin Nam, Cynthia A. Bradham, Michael Dean, Joseph Chacko, Anthony J. Robertson, Margherita Branno, Valeria Matranga, K. James Durbin, Esther Miranda, Lili Chen, Eran Elhaik, Robert D. Burke, Rita A. Wright, Paola Oliveri, Sandra L. Lee, Gary W. Moy, Alexander E Primus, Shawn S. McCafferty, Cristina Calestani, David A. Garfield, Erica Sodergren, Karen Wilson, Joel Smith, Marco A. Marra, Cynthia Messier, Julia Morales, Kim D. Pruitt, Rachel Thorn, Rachel Gill, John S. Taylor, Mark E. Hahn, Victor Sapojnikov, Meredith Howard-Ashby, Lynne M. Angerer, Maurice R. Elphick, Kathy R. Foltz, Anne Marie Genevière, Justin T. Reese, Blanca E. Galindo, Kim C. Worley, Andrew Leone, Glen Humphrey, Kevin Berney, Olga Ermolaeva, George Miner, David P. Terwilliger, Elly Suk Hen Chow, Lora Lewis, Dan Graur, C. Titus Brown, Gerard Manning, Kevin J. Peterson, Angela Jolivet, Michele K. Anderson, Francesca Rizzo, Ekaterina Voronina, Thierry Lepage, Giorgio Matassi, Antonio Fernandez-Guerra, Mamoru Nomura, Charles A. Whittaker, James R.R. Whittle, James A. Coffman, George M. Weinstock, Mohammed M. Idris, Ashlan M. Musante, Sebastian D. Fugmann, Katherine D. Walton, Sorin Istrail, Shu-Yu Wu, Cerrissa Hamilton, Jonah Cool, Jacqueline E. Schein, Stacey M. Curry, Athula Wikramanayke, Seth Carbonneau, Blair J. Rossetti, Christopher E. Killian, Melissa J. Landrum, Amanda P. Rawson, Jenifer C. Croce, Ryan C. Range, Rahul Satija, John J. Stegeman, Yufeng Shen, Cavit Agca, Terry Gaasterland, Rocky Cheung, Takae Kiyama, Nikki Adams, Jonathan P. Rast, Robert Piotr Olinski, Andrew Cree, Mark Scally, Shuguang Liang, David A. Parker, Rebecca Thomason, Gretchen E. Hofmann, Michelle M. Roux, Ronghui Xu, Robert A. Obar, Enrique Arboleda, Odile Mulner-Lorillon, Shannon Dugan-Rocha, David J. Bottjer, Gabriele Amore, Manoj P. Samanta, Waraporn Tongprasit, Véronique Duboc, La Ronda Jackson, Fred H. Wilt, Viktor Stolc, Anna T. Neill, Michael Raisch, Pei Yun Lee, Jia L. Song, Margaret Morgan, Brian T. Livingston, Sofia Hussain, Zheng Wei, Bryan J. Cole, Tonya F. Severson, Victor V. Solovyev, Finn Hallböök, Donna M. Muzny, Christine A. Byrum, Albert J. Poustka, Xiuqian Mu, Andrew R. Jackson, Shin Heesun, Euan R. Brown, Nansheng Chen, Patrick Cormier, Ralph Haygood, Pedro Martinez, R. Andrew Cameron, D. Wang, Wendy S. Beane, Eric H. Davidson, Christie Kovar, Hemant Kelkar, Charles A. Ettensohn, Sham V. Nair, Robert L. Morris, Stefan C. Materna, Michael C. Thorndyke, Richard A. Gibbs, Dan O Mellott, Department of Physiology and Biophysics, Stony Brook University [The State University of New York] ( SBU ), Astronomy Unit ( AU ), Queen Mary University of London ( QMUL ), Urban and Industrial Air Quality Group, CSIRO Energy Technology, Commonwealth Scientific and Industrial Research Organisation Energy Technology ( CSIRO Energy Technology ), Commonwealth Scientific and Industrial Research Organisation, Center for Polymer Studies ( CPS ), Boston University [Boston] ( BU ), Physics Department [Boston] ( BU-Physics ), Max Planck Institute for Psycholinguistics, Max-Planck-Institut, Department of Biology [Norton], Wheaton College [Norton], Mathematical Institute [Oxford] ( MI ), University of Oxford [Oxford], Centre for the Analysis of Time Series ( CATS ), London School of Economics and Political Science ( LSE ), Thomas Jefferson National Accelerator Facility ( Jefferson Lab ), Thomas Jefferson National Accelerator Facility, Laboratoire d'Energétique et de Mécanique Théorique Appliquée ( LEMTA ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Evolution, Génomes et Spéciation ( LEGS ), Centre National de la Recherche Scientifique ( CNRS ), Department of Geology, University of Illinois at Urbana-Champaign [Urbana], Department of Electrical and Computer Engineering [Portland] ( ECE ), Portland State University [Portland] ( PSU ), Saint-Gobain Crystals [USA], SAINT-GOBAIN, Institute for Animal Health ( IAH ), Biotechnology and Biological Sciences Research Council, Center for Agricultural Resources Research, Chinese Academy of Sciences [Changchun Branch] ( CAS ), Ipsen Inc. [Milford] ( Ipsen ), IPSEN, Department of Physics [Berkeley], University of California [Berkeley], Institute for Climate and Atmospheric Science [Leeds] ( ICAS ), University of Leeds, Chung-Ang University ( CAU ), Chung-Ang University [Seoul], Antarctic Climate and Ecosystems Cooperative Research Center ( ACE-CRC ), Institute of Aerodynamics and Fluid Mechanics ( AER ), Technische Universität München [München] ( TUM ), Mer et santé ( MS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Imperial College London, Radio and Atmospheric Sciences Division, National Physical Laboratory [Teddington] ( NPL ), International Research Institute for Climate and Society ( IRI ), Earth Institute at Columbia University, Columbia University [New York]-Columbia University [New York], Soils Group, The Macaulay Institute, Department of Haematology, University of Cambridge [UK] ( CAM ), School of Biology and Biochemistry, Queen's University, Leslie Hill Institute for Plant Conservation ( PCU ), University of Cape Town, Institute for Microelectronics and Microsystems/ Istituto per la Microelettronica e Microsistemi ( IMM ), Consiglio Nazionale delle Ricerche ( CNR ), Laboratoire d'acoustique de l'université du Mans ( LAUM ), Le Mans Université ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Interactive Systems Labs ( ISL ), Carnegie Mellon University [Pittsburgh] ( CMU ), Dalian Institute of Chemical Physics ( DICP ), Architectures, Languages and Compilers to Harness the End of Moore Years ( ALCHEMY ), Laboratoire de Recherche en Informatique ( LRI ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ) -Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique ( Inria ), Clean Air Task Force ( CATF ), Clean Air Task Force, Space Physics Laboratory, Indian Space Research Organisation ( ISRO ), Centre d'études et de recherches appliquées à la gestion ( CERAG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Microbiology and Immunology, College of Medicine and Health Sciences-Sultan Qaboos University, European Molecular Biology Laboratory [Heidelberg] ( EMBL ), Department of Biostatistics, University of Michigan [Ann Arbor], Department of Radiation Oncology [Michigan] ( Radonc ), Department of Physics and Astronomy [Leicester], University of Leicester, Informatique, Biologie Intégrative et Systèmes Complexes ( IBISC ), Université d'Évry-Val-d'Essonne ( UEVE ) -Centre National de la Recherche Scientifique ( CNRS ), Institut für Meteorologie und Klimaforschung ( IMK ), Karlsruher Institut für Technologie ( KIT ), Physics Department [UNB], University of New Brunswick ( UNB ), Laboratoire Parole et Langage ( LPL ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Biogéosciences [Dijon] ( BGS ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Bioprojet, Laboratoire de Matériaux à Porosité Contrôlée ( LMPC ), Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Ecole Nationale Supérieure de Chimie de Mulhouse-Centre National de la Recherche Scientifique ( CNRS ), School of Information Engineering [USTB] ( SIE ), University of Science and Technology Beijing [Beijing] ( USTB ), Laboratory for Atmospheric and Space Physics [Boulder] ( LASP ), University of Colorado Boulder [Boulder], Department of Applied Mathematics [Sheffield], University of Sheffield [Sheffield], School of Mathematics and Statistics [Sheffield] ( SoMaS ), Laboratoire de Mécanique de Lille - FRE 3723 ( LML ), Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department [UCLA] ( CSD ), University of California at Los Angeles [Los Angeles] ( UCLA ), Développement et évolution ( DE ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biologie du Développement de Villefranche sur mer ( LBDV ), Laboratoire Pierre Aigrain ( LPA ), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris ( FRDPENS ), Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Mathematics and Statistics [Mac Gill], McGill University, Departamento de Botánica [Comahue], Universidad nacional del Comahue, Bioénergétique Cellulaire et Pathologique ( BECP ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Environnements et Paléoenvironnements OCéaniques ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratori Nazionali del Sud ( LNS ), National Institute for Nuclear Physics ( INFN ), Departament de Matemàtiques [Barcelona], Universitat Autònoma de Barcelona [Barcelona] ( UAB ), Max-Planck-Institut für Kohlenforschung (coal research), Institute of Oceanology [CAS] ( IOCAS ), National Chiao Tung University ( NCTU ), Department of Hydrology and Water Resources ( HWR ), University of Arizona, Centre for Educational Technology, Environment Department [York], University of York [York, UK], State Key Laboratory of Nuclear Physics and Technology ( SKL-NPT ), Peking University [Beijing], Department of Physics and Astronomy [Iowa City], University of Iowa [Iowa], NASA Ames Research Center ( ARC ), Department of Materials, Digital Language & Knowledge Contents Research Association ( DICORA ), Hankuk University of Foreign Studies, Department of Physics [Coventry], University of Warwick [Coventry], Space Science and Technology Department [Didcot] ( RAL Space ), STFC Rutherford Appleton Laboratory ( RAL ), Science and Technology Facilities Council ( STFC ) -Science and Technology Facilities Council ( STFC ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), H M Nautical Almanac Office [RAL] ( HMNAO ), Rutherford Appleton Laboratory, United Kingdom Met Office [Exeter], University College of London [London] ( UCL ), Department of Pathology and Laboratory Medicine [UCLA], University of California at Los Angeles [Los Angeles] ( UCLA ) -School of Medicine, School of Earth and Environmental Sciences [Seoul] ( SEES ), Seoul National University [Seoul], Department of Chemistry, Seoul Women's University, MicroMachines Centre ( MMC ), Nanyang Technological University [Singapour], Regroupement Québécois sur les Matériaux de Pointe ( RQMP ), École Polytechnique de Montréal ( EPM ) -Université de Sherbrooke [Sherbrooke]-McGill University-Université de Montréal-Fonds Québécois de Recherche sur la Nature et les Technologies ( FQRNT ), Département de Physique [Montréal], Université de Montréal, School of Earth and Environment [Leeds] ( SEE ), Centre for Ecology and Hydrology ( CEH ), Natural Environment Research Council ( NERC ), Norwegian Institute for Water Research ( NIVA ), Norwegian Institute for Water Research, Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY), Astronomy Unit [London] (AU), Queen Mary University of London (QMUL), Commonwealth Scientific and Industrial Research Organisation Energy Technology (CSIRO Energy Technology), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Department of Biochemistry and Molecular Biology [Houston], The University of Texas Medical School at Houston, Mathematical Institute [Oxford] (MI), University of Oxford, Centre for the Analysis of Time Series (CATS), London School of Economics and Political Science (LSE), Thomas Jefferson National Accelerator Facility (Jefferson Lab), Laboratoire Énergies et Mécanique Théorique et Appliquée (LEMTA ), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Evolution, Génomes et Spéciation (LEGS), Centre National de la Recherche Scientifique (CNRS), University of Illinois System-University of Illinois System, Department of Electrical and Computer Engineering [Portland] (ECE), Portland State University [Portland] (PSU), Saint-Gobain, Institute for Animal Health (IAH), Biotechnology and Biological Sciences Research Council (BBSRC), Chinese Academy of Sciences [Changchun Branch] (CAS), Ipsen Inc. [Milford] (Ipsen), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Institute for Climate and Atmospheric Science [Leeds] (ICAS), School of Earth and Environment [Leeds] (SEE), University of Leeds-University of Leeds, Chung-Ang University (CAU), Antarctic Climate and Ecosystems Cooperative Research Centre (ACE-CRC), Institute of Aerodynamics and Fluid Mechanics (AER), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Mer et santé (MS), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), National Physical Laboratory [Teddington] (NPL), International Research Institute for Climate and Society (IRI), Macaulay Institute, University of Cambridge [UK] (CAM), Queen's University [Kingston, Canada], Leslie Hill Institute for Plant Conservation (PCU), Istituto per la Microelettronica e Microsistemi [Catania] (IMM), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Laboratoire d'Acoustique de l'Université du Mans (LAUM), Le Mans Université (UM)-Centre National de la Recherche Scientifique (CNRS), Interactive Systems Labs (ISL), Carnegie Mellon University [Pittsburgh] (CMU), Dalian Institute of Chemical Physics (DICP), Architectures, Languages and Compilers to Harness the End of Moore Years (ALCHEMY), Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Clean Air Task Force (CATF), Indian Space Research Organisation (ISRO), Centre d'études et de recherches appliquées à la gestion (CERAG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Centre National de la Recherche Scientifique (CNRS), Sultan Qaboos University (SQU)-College of Medicine and Health Sciences [Baylor], Baylor University-Baylor University, European Molecular Biology Laboratory [Heidelberg] (EMBL), University of Michigan System-University of Michigan System, Department of Radiation Oncology [Michigan] (Radonc), Informatique, Biologie Intégrative et Systèmes Complexes (IBISC), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Institute for Meteorology and Climate Research (IMK), Karlsruhe Institute of Technology (KIT), University of New Brunswick (UNB), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Matériaux à Porosité Contrôlée (LMPC), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS), School of Information Engineering [USTB] (SIE), University of Science and Technology Beijing [Beijing] (USTB), Laboratory for Atmospheric and Space Physics [Boulder] (LASP), University of Colorado [Boulder], School of Mathematics and Statistics [Sheffield] (SoMaS), Laboratoire de Mécanique de Lille - FRE 3723 (LML), Université de Lille, Sciences et Technologies-Centrale Lille-Centre National de la Recherche Scientifique (CNRS), Computer Science Department [UCLA] (CSD), University of California [Los Angeles] (UCLA), Développement et évolution (DE), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Observatoire océanologique de Villefranche-sur-mer (OOVM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Pierre Aigrain (LPA), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Mathematics and Statistics [Montréal], McGill University = Université McGill [Montréal, Canada], Departamento de Botánica [Bariloche], Centro Regional Universitario Bariloche [Bariloche] (CRUB), Universidad Nacional del Comahue [Neuquén] (UNCOMA)-Universidad Nacional del Comahue [Neuquén] (UNCOMA), Bioénergétique Cellulaire et Pathologique (BECP), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Environnements et Paléoenvironnements OCéaniques (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratori Nazionali del Sud (LNS), Istituto Nazionale di Fisica Nucleare (INFN), Departament de Matemàtiques [Barcelona] (UAB), Universitat Autònoma de Barcelona (UAB), Max-Planck-Institut für Kohlenforschung (Coal Research), Max-Planck-Gesellschaft, CAS Institute of Oceanology (IOCAS), Chinese Academy of Sciences [Beijing] (CAS), National Chiao Tung University (NCTU), Department of Hydrology and Water Resources (HWR), State Key Laboratory of Nuclear Physics and Technology (SKL-NPT), University of Iowa [Iowa City], NASA Ames Research Center (ARC), Digital Language & Knowledge Contents Research Association (DICORA), Space Science and Technology Department [Didcot] (RAL Space), STFC Rutherford Appleton Laboratory (RAL), Science and Technology Facilities Council (STFC)-Science and Technology Facilities Council (STFC), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), H M Nautical Almanac Office [RAL] (HMNAO), University College of London [London] (UCL), University of California (UC)-University of California (UC)-School of Medicine, School of Earth and Environmental Sciences [Seoul] (SEES), Seoul National University [Seoul] (SNU), MicroMachines Centre (MMC), Regroupement Québécois sur les Matériaux de Pointe (RQMP), École Polytechnique de Montréal (EPM)-Université de Sherbrooke (UdeS)-McGill University = Université McGill [Montréal, Canada]-Université de Montréal (UdeM)-Fonds Québécois de Recherche sur la Nature et les Technologies (FQRNT), Université de Montréal (UdeM), Centre for Ecology and Hydrology (CEH), Natural Environment Research Council (NERC), Norwegian Institute for Water Research (NIVA), SEA URCHIN GENOME SEQUENCING CONSORTIUM, SODERGREN E, WEINSTOCK GM, DAVIDSON EH, CAMERON RA, GIBBS RA, ANGERER RC, ANGERER LM, ARNONE MI, BURGESS DR, BURKE RD, COFFMAN JA, DEAN M, ELPHICK MR, ETTENSOHN CA, FOLTZ KR, HAMDOUN A, HYNES RO, KLEIN WH, MARZLUFF W, MCCLAY DR, MORRIS RL, MUSHEGIAN A, RAST JP, SMITH LC, THORNDYKE MC, VACQUIER VD, WESSEL GM, WRAY G, ZHANG L, ELSIK CG, ERMOLAEVA O, HLAVINA W, HOFMANN G, KITTS P, LANDRUM MJ, MACKEY AJ, MAGLOTT D, PANOPOULOU G, POUSTKA AJ, PRUITT K, SAPOJNIKOV V, SONG X, SOUVOROV A, SOLOVYEV V, WEI Z, WHITTAKER CA, WORLEY K, DURBIN KJ, SHEN Y, FEDRIGO O, GARFIELD D, HAYGOOD R, PRIMUS A, SATIJA R, SEVERSON T, GONZALEZ-GARAY ML, JACKSON AR, MILOSAVLJEVIC A, TONG M, KILLIAN CE, LIVINGSTON BT, WILT FH, ADAMS N, BELLE R, CARBONNEAU S, CHEUNG R, CORMIER P, COSSON B, CROCE J, FERNANDEZ-GUERRA A, GENEVIERE AM, GOEL M, KELKAR H, MORALES J, MULNER-LORILLON O, ROBERTSON AJ, GOLDSTONE JV, COLE B, EPEL D, GOLD B, HAHN ME, HOWARD-ASHBY M, SCALLY M, STEGEMAN JJ, ALLGOOD EL, COOL J, JUDKINS KM, MCCAFFERTY SS, MUSANTE AM, OBAR RA, RAWSON AP, ROSSETTI BJ, GIBBONS IR, HOFFMAN MP, LEONE A, ISTRAIL S, MATERNA SC, SAMANTA MP, STOLC V, TONGPRASIT W, TU Q, BERGERON KF, BRANDHORST BP, WHITTLE J, BERNEY K, BOTTJER DJ, CALESTANI C, PETERSON K, CHOW E, YUAN QA, ELHAIK E, GRAUR D, REESE JT, BOSDET I, HEESUN S, MARRA MA, SCHEIN J, ANDERSON MK, BROCKTON V, BUCKLEY KM, COHEN AH, FUGMANN SD, HIBINO T, LOZA-COLL M, MAJESKE AJ, MESSIER C, NAIR SV, PANCER Z, TERWILLIGER DP, AGCA C, ARBOLEDA E, CHEN N, CHURCHER AM, HALLBOOK F, HUMPHREY GW, IDRIS MM, KIYAMA T, LIANG S, MELLOTT D, MU X, MURRAY G, OLINSKI RP, RAIBLE F, ROWE M, TAYLOR JS, TESSMAR-RAIBLE K, WANG D, WILSON KH, YAGUCHI S, GAASTERLAND T, GALINDO BE, GUNARATNE HJ, JULIANO C, KINUKAWA M, MOY GW, NEILL AT, NOMURA M, RAISCH M, READE A, ROUX MM, SONG JL, SU YH, TOWNLEY IK, VORONINA E, WONG JL, AMORE G, BRANNO M, BROWN ER, CAVALIERI, V, DUBOC V, DULOQUIN L, FLYTZANIS C, GACHE C, LAPRAZ F, LEPAGE T, LOCASCIO A, MART, University of California-University of California, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Le Mans Université (UM), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ecole Nationale Supérieure de Chimie de Mulhouse-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), University of California-University of California-School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), University of Manchester Institute of Science and Technology (UMIST), Condensed Matter Physics and Materials Science Department, Brookhaven National Laboratory, Brookhaven National Laboratory [Upton, NY] (BNL), UT-Battelle, LLC-Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY)-U.S. Department of Energy [Washington] (DOE)-UT-Battelle, LLC-Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY)-U.S. Department of Energy [Washington] (DOE), Baylor College of Medicine (BCM), Baylor University, Laboratoire de Traitement de l'Information Medicale (LaTIM), Université européenne de Bretagne - European University of Brittany (UEB)-Université de Brest (UBO)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Modélisation et Simulation Multi Echelle (MSME), Université Paris-Est Marne-la-Vallée (UPEM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Duke University [Durham], Instituto Andaluz de Geofísica y Prevención de Desastres Sísmicos [Granada] (IAGPDS), Universidad de Granada (UGR), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), University of New South Wales [Sydney] (UNSW), Celera Genomics (CRA), Celera Genomics, Paléobiodiversité et paléoenvironnements, Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma Tor Vergata [Roma], Unité de recherches forestières (BORDX PIERR UR ), Institut National de la Recherche Agronomique (INRA), Deptartment of Neuroscience, Uppsala University, State Key Laboratory of Palaeobiology and Stratigraphy, Nanjing Institute of Geology and Palaeontology (NIGPAS-CAS), Chinese Academy of Sciences [Nanjing Branch]-Chinese Academy of Sciences [Nanjing Branch], Institut Méditerranéen d'Ecologie et de Paléoécologie (IMEP), Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Avignon Université (AU)-Centre National de la Recherche Scientifique (CNRS), Key Laboratory of Ocean Circulation and Waves, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China, Université Paris Diderot - Paris 7 (UPD7), Department of Physical and Environmental Sciences [Toronto], University of Toronto at Scarborough, inconnu temporaire UPEMLV, Inconnu, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Department of Atmospheric Sciences [Seattle], University of Washington [Seattle], National Institute of Advanced Industrial Science and Technology (AIST), Department of Pharmacy, Università degli studi di Genova = University of Genoa (UniGe), Interdisciplinary Arts and Sciences Department, St. Vincent's Hospital, Sydney, Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Electrical Engineering (DEE-POSTECH), Pohang University of Science and Technology (POSTECH), Centre Suisse d'Electronique et de Microtechnique SA [Neuchatel] (CSEM), Centre Suisse d'Electronique et Microtechnique SA (CSEM), Human Genome Sequencing Center [Houston] (HGSC), Brookhaven National Laboratory, Meteorological Service of Canada, 4905 Dufferin Street, Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mines-Télécom [Paris] (IMT), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Marne-la-Vallée (UPEM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherches Forestières, Department of Physical and Environmental Sciences, University of Toronto [Scarborough, Canada], National Institute for Nuclear Physics (INFN), University of Genoa (UNIGE), Institut de Recherche pour le Développement (IRD)-Institut Universitaire Européen de la Mer (IUEM), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Université de Brest (UBO)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Universidad de Granada = University of Granada (UGR), Laboratoire d'Energétique et de Mécanique Théorique Appliquée (LEMTA ), Technische Universität München [München] (TUM), Queen's University [Kingston], Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Grenoble Alpes (UGA), Institut für Meteorologie und Klimaforschung (IMK), Karlsruher Institut für Technologie (KIT), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Universitat Autònoma de Barcelona [Barcelona] (UAB), École Polytechnique de Montréal (EPM)-Université de Sherbrooke [Sherbrooke]-Université de Montréal [Montréal]-McGill University-Fonds Québécois de Recherche sur la Nature et les Technologies (FQRNT), Université de Montréal [Montréal], U.S. Department of Energy [Washington] (DOE)-UT-Battelle, LLC-Stony Brook University [SUNY] (SBU), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paul Cézanne - Aix-Marseille 3-Centre National de la Recherche Scientifique (CNRS)-Avignon Université (AU)-Université de Provence - Aix-Marseille 1, Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Brest (UBO), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Signal Transduction, MESH: Sequence Analysis, DNA, MESH : Transcription Factors, MESH : Calcification, Physiologic, Genome, MESH : Proteins, 0302 clinical medicine, MESH : Embryonic Development, MESH: Gene Expression Regulation, Developmental, Innate, MESH: Embryonic Development, Developmental, Nervous System Physiological Phenomena, MESH: Animals, MESH: Proteins, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Complement Activation, ComputingMilieux_MISCELLANEOUS, MESH: Evolution, Molecular, MESH : Strongylocentrotus purpuratus, Genetics, 0303 health sciences, MESH: Nervous System Physiological Phenomena, Multidisciplinary, biology, Medicine (all), MESH: Immunologic Factors, Gene Expression Regulation, Developmental, Genome project, MESH: Transcription Factors, MESH : Immunity, Innate, MESH : Complement Activation, MESH: Genes, Bacterial artificial chromosome (BAC)DeuterostomesStrongylocentrotus purpuratusVertebrate innovations, Echinoderm, MESH : Nervous System Physiological Phenomena, embryonic structures, MESH: Cell Adhesion Molecules, MESH : Genes, MESH: Immunity, Innate, Sequence Analysis, Signal Transduction, MESH: Computational Biology, Genome evolution, MESH: Complement Activation, Sequence analysis, Evolution, MESH: Strongylocentrotus purpuratus, MESH : Male, Embryonic Development, MESH : Immunologic Factors, Article, MESH: Calcification, Physiologic, Calcification, MESH : Cell Adhesion Molecules, Evolution, Molecular, 03 medical and health sciences, Calcification, Physiologic, Animals, Immunologic Factors, MESH: Genome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Evolution, Molecular, Physiologic, Gene, Strongylocentrotus purpuratus, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH : Signal Transduction, Bacterial artificial chromosome, Immunity, Molecular, Computational Biology, Proteins, Cell Adhesion Molecules, Genes, Immunity, Innate, Transcription Factors, Sequence Analysis, DNA, DNA, biology.organism_classification, MESH: Male, Gene Expression Regulation, MESH : Animals, MESH : Gene Expression Regulation, Developmental, MESH : Genome, 030217 neurology & neurosurgery, MESH : Computational Biology, MESH : Sequence Analysis, DNA
Abstract: We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus , a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
Published: 2006

33. Dominance of Sulfurospirillum in Metagenomes Associated with the Methane Ice Worm (Sirsoe methanicola).

Author: Lim SJ, Thompson LR, Young CM, Gaasterland T, and Goodwin KD
Subjects: Animals, Bacteria, Carbon metabolism, Humans, Methane metabolism, Phylogeny, RNA, Ribosomal, 16S genetics, RNA, Ribosomal, 16S metabolism, Sulfides metabolism, Metagenome, Polychaeta metabolism
Abstract: Sirsoe methanicola, commonly known as the methane ice worm, is the only macrofaunal species known to inhabit the Gulf of Mexico methane hydrates. Little is known about this elusive marine polychaete that can colonize rich carbon and energy reserves. Metagenomic analysis of gut contents and worm fragments predicted diverse metabolic capabilities with the ability to utilize a range of nitrogen, sulfur, and organic carbon compounds through microbial taxa affiliated with Campylobacterales , Desulfobacterales , Enterobacterales , SAR324 , Alphaproteobacteria , and Mycoplasmatales . Entomoplasmatales and Chitinivibrionales were additionally identified from extracted full-length 16S rRNA sequences, and read analysis identified 196 bacterial families. Overall, the microbial community appeared dominated by uncultured Sulfurospirillum , a taxon previously considered free-living rather than host-associated. Metagenome-assembled genomes (MAGs) classified as uncultured Sulfurospirillum predicted thiosulfate disproportionation and the reduction of tetrathionate, sulfate, sulfide/polysulfide, and nitrate. Microbial amino acid and vitamin B12 biosynthesis genes were identified in multiple MAGs, suggesting nutritional value to the host. Reads assigned to aerobic or anaerobic methanotrophic taxa were rare. IMPORTANCE Methane hydrates represent vast reserves of natural gas with roles in global carbon cycling and climate change. This study provided the first analysis of metagenomes associated with Sirsoe methanicola, the only polychaete species known to colonize methane hydrates. Previously unrecognized participation of Sulfurospirillum in a gut microbiome is provided, and the role of sulfur compound redox reactions within this community is highlighted. The comparative biology of S. methanicola is of general interest given research into the adverse effects of sulfide production in human gut microbiomes. In addition, taxonomic assignments are provided for nearly 200 bacterial families, expanding our knowledge of microbiomes in the deep sea.
Published: 2022
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34. Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids.

Author: Lee S, Mendoza TR, Burner DN, Muldong MT, Wu CCN, Arreola-Villanueva C, Zuniga A, Greenburg O, Zhu WY, Murtadha J, Koutouan E, Pineda N, Pham H, Kang SG, Kim HT, Pineda G, Lennon KM, Cacalano NA, Jamieson CHM, Kane CJ, Kulidjian AA, Gaasterland T, and Jamieson CAM
Subjects: Androgens pharmacology, Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 metabolism, Animals, Benzamides pharmacology, Bone Neoplasms metabolism, Bone Neoplasms secondary, COVID-19 genetics, COVID-19 metabolism, COVID-19 virology, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Nitriles pharmacology, Phenylthiohydantoin pharmacology, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Virus genetics, Receptors, Virus metabolism, SARS-CoV-2 metabolism, SARS-CoV-2 physiology, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Transplantation, Heterologous, Virus Internalization, Bone Neoplasms genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic genetics, Organoids metabolism, Prostatic Neoplasms, Castration-Resistant genetics
Abstract: Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.
Published: 2022
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35. A Machine Learning Method to Identify Genetic Variants Potentially Associated With Alzheimer's Disease.

Author: Monk B, Rajkovic A, Petrus S, Rajkovic A, Gaasterland T, and Malinow R
Abstract: There is hope that genomic information will assist prediction, treatment, and understanding of Alzheimer's disease (AD). Here, using exome data from ∼10,000 individuals, we explore machine learning neural network (NN) methods to estimate the impact of SNPs (i.e., genetic variants) on AD risk. We develop an NN-based method (netSNP) that identifies hundreds of novel potentially protective or at-risk AD-associated SNPs (along with an effect measure); the majority with frequency under 0.01. For case individuals, the number of "protective" (or "at-risk") netSNP-identified SNPs in their genome correlates positively (or inversely) with their age of AD diagnosis and inversely (or positively) with autopsy neuropathology. The effect measure increases correlations. Simulations suggest our results are not due to genetic linkage, overfitting, or bias introduced by netSNP. These findings suggest that netSNP can identify SNPs associated with AD pathophysiology that may assist with the diagnosis and mechanistic understanding of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Monk, Rajkovic, Petrus, Rajkovic, Gaasterland and Malinow.)
Published: 2021
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36. Dynamic transcriptome landscape in the song nucleus HVC between juvenile and adult zebra finches.

Author: Shi Z, Zhang Z, Schaffer L, Huang Z, Fu L, Head S, Gaasterland T, Wang XJ, and Li X
Abstract: Male juvenile zebra finches learn to sing by imitating songs of adult males early in life. The development of the song control circuit and song learning and maturation are highly intertwined processes, involving gene expression, neurogenesis, circuit formation, synaptic modification, and sensory-motor learning. To better understand the genetic and genomic mechanisms underlying these events, we used RNA-Seq to examine genome-wide transcriptomes in the song control nucleus HVC of male juvenile (45 d) and adult (100 d) zebra finches. We report that gene groups related to axon guidance, RNA processing, lipid metabolism, and mitochondrial functions show enriched expression in juvenile HVC compared to the rest of the brain. As juveniles mature into adulthood, massive gene expression changes occur. Expression of genes related to amino acid metabolism, cell cycle, and mitochondrial function is reduced, accompanied by increased and enriched expression of genes with synaptic functions, including genes related to G-protein signaling, neurotransmitter receptors, transport of small molecules, and potassium channels. Unexpectedly, a group of genes with immune system functions is also developmentally regulated, suggesting potential roles in the development and functions of HVC. These data will serve as a rich resource for investigations into the development and function of a neural circuit that controls vocal behavior., Competing Interests: All authors declare no conflict of interest., (© 2020 The Authors. Advanced Genetics published by Wiley Periodicals LLC.)
Published: 2021
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37. Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells.

Author: Gumber D, Do M, Suresh Kumar N, Sonavane PR, Wu CCN, Cruz LS, Grainger S, Carson D, Gaasterland T, and Willert K
Subjects: Blotting, Western, Gene Expression Regulation, Humans, Mesoderm cytology, Mesoderm growth & development, Real-Time Polymerase Chain Reaction, Recombinant Proteins, Wnt Signaling Pathway physiology, Cell Differentiation physiology, Frizzled Receptors physiology, Mesoderm embryology, Pluripotent Stem Cells physiology
Abstract: WNT proteins are secreted symmetry breaking signals that interact with cell surface receptors of the FZD family to regulate a multitude of developmental processes. Studying selectivity between WNTs and FZDs has been hampered by the paucity of purified WNT proteins and by their apparent non-selective interactions with the FZD receptors. Here, we describe an engineered protein, called F7L6, comprised of antibody-derived single-chain variable fragments, that selectively binds to human FZD7 and the co-receptor LRP6. F7L6 potently activates WNT/β-catenin signaling in a manner similar to Wnt3a. In contrast to Wnt3a, F7L6 engages only FZD7 and none of the other FZD proteins. Treatment of human pluripotent stem (hPS) cells with F7L6 initiates transcriptional programs similar to those observed during primitive streak formation and subsequent gastrulation in the mammalian embryo. This demonstrates that selective engagement and activation of FZD7 signaling is sufficient to promote mesendodermal differentiation of hPS cells., Competing Interests: DG, MD, NS, PS, CW, LC, SG, DC, TG, KW No competing interests declared, (© 2020, Gumber et al.)
Published: 2020
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38. Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7.

Author: Stoyas CA, Bushart DD, Switonski PM, Ward JM, Alaghatta A, Tang MB, Niu C, Wadhwa M, Huang H, Savchenko A, Gariani K, Xie F, Delaney JR, Gaasterland T, Auwerx J, Shakkottai VG, and La Spada AR
Subjects: Animals, Cell Line, Cerebellum metabolism, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Signal Transduction physiology, Sirtuin 1 genetics, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias prevention & control, Calcium physiology, Homeostasis physiology, Neuroprotection physiology, Niacinamide metabolism, Sirtuin 1 metabolism, Spinocerebellar Ataxias metabolism
Abstract: Sirtuin 1 (Sirt1) is a NAD + -dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD + depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD + repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD + dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)
Published: 2020
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39. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Author: Bailey JNC, Gharahkhani P, Kang JH, Butkiewicz M, Sullivan DA, Weinreb RN, Aschard H, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP Jr, Song YE, Hark L, Ritch R, Rhee DJ, Vollrath D, Zack DJ, Medeiros F, Vajaranant TS, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Craig JE, Burdon KP, Hewitt AW, Mackey DA, Haines JL, MacGregor S, Wiggs JL, and Pasquale LR
Subjects: Datasets as Topic, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Intraocular Pressure physiology, Low Tension Glaucoma genetics, Male, Middle Aged, Glaucoma, Open-Angle genetics, Metabolic Networks and Pathways genetics, Polymorphism, Single Nucleotide, Testosterone metabolism
Abstract: Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk., Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG])., Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations., Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
Published: 2018
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40. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis.

Author: Aschard H, Kang JH, Iglesias AI, Hysi P, Cooke Bailey JN, Khawaja AP, Allingham RR, Ashley-Koch A, Lee RK, Moroi SE, Brilliant MH, Wollstein G, Schuman JS, Fingert JH, Budenz DL, Realini T, Gaasterland T, Scott WK, Singh K, Sit AJ, Igo RP Jr, Song YE, Hark L, Ritch R, Rhee DJ, Gulati V, Haven S, Vollrath D, Zack DJ, Medeiros F, Weinreb RN, Cheng CY, Chasman DI, Christen WG, Pericak-Vance MA, Liu Y, Kraft P, Richards JE, Rosner BA, Hauser MA, Klaver CCW, vanDuijn CM, Haines J, Wiggs JL, and Pasquale LR
Subjects: Female, Genetic Predisposition to Disease, Humans, Male, Blood Pressure genetics, Glaucoma, Open-Angle genetics, Intraocular Pressure genetics, Linkage Disequilibrium
Abstract: Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10 -27 ) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10 -5 ); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.
Published: 2017
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41. The WNT target SP5 negatively regulates WNT transcriptional programs in human pluripotent stem cells.

Author: Huggins IJ, Bos T, Gaylord O, Jessen C, Lonquich B, Puranen A, Richter J, Rossdam C, Brafman D, Gaasterland T, and Willert K
Subjects: Cell Line, DNA-Binding Proteins genetics, Gene Expression Regulation, Humans, Pluripotent Stem Cells cytology, Transcription Factors genetics, Wnt Signaling Pathway, Wnt3A Protein genetics, beta Catenin genetics, beta Catenin metabolism, DNA-Binding Proteins metabolism, Pluripotent Stem Cells metabolism, Transcription Factors metabolism, Wnt3A Protein metabolism
Abstract: The WNT/β-catenin signaling pathway is a prominent player in many developmental processes, including gastrulation, anterior-posterior axis specification, organ and tissue development, and homeostasis. Here, we use human pluripotent stem cells (hPSCs) to study the dynamics of the transcriptional response to exogenous activation of the WNT pathway. We describe a mechanism involving the WNT target gene SP5 that leads to termination of the transcriptional program initiated by WNT signaling. Integration of gene expression profiles of wild-type and SP5 mutant cells with genome-wide SP5 binding events reveals that SP5 acts to diminish expression of genes previously activated by the WNT pathway. Furthermore, we show that activation of SP5 by WNT signaling is most robust in cells with developmental potential, such as stem cells. These findings indicate a mechanism by which the developmental WNT signaling pathway reins in expression of transcriptional programs.
Published: 2017
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42. ISCB's initial reaction to New England Journal of Medicine editorial on data sharing.

Author: Berger B, Gaasterland T, Lengauer T, Orengo CA, Gaeta B, Markel S, and Valencia A
Subjects: Humans, Periodicals as Topic, Publishing, Editorial Policies, Information Dissemination
Published: 2017
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43. Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses.

Author: Khawaja AP, Cooke Bailey JN, Kang JH, Allingham RR, Hauser MA, Brilliant M, Budenz DL, Christen WG, Fingert J, Gaasterland D, Gaasterland T, Kraft P, Lee RK, Lichter PR, Liu Y, Medeiros F, Moroi SE, Richards JE, Realini T, Ritch R, Schuman JS, Scott WK, Singh K, Sit AJ, Vollrath D, Wollstein G, Zack DJ, Zhang K, Pericak-Vance M, Weinreb RN, Haines JL, Pasquale LR, and Wiggs JL
Abstract: Purpose: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins., Methods: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure., Results: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010)., Conclusions: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.
Published: 2016
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44. A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium.

Author: Liu Y, Bailey JC, Helwa I, Dismuke WM, Cai J, Drewry M, Brilliant MH, Budenz DL, Christen WG, Chasman DI, Fingert JH, Gaasterland D, Gaasterland T, Gordon MO, Igo RP Jr, Kang JH, Kass MA, Kraft P, Lee RK, Lichter P, Moroi SE, Realini A, Richards JE, Ritch R, Schuman JS, Scott WK, Singh K, Sit AJ, Song YE, Vollrath D, Weinreb R, Medeiros F, Wollstein G, Zack DJ, Zhang K, Pericak-Vance MA, Gonzalez P, Stamer WD, Kuchtey J, Kuchtey RW, Allingham RR, Hauser MA, Pasquale LR, Haines JL, and Wiggs JL
Subjects: Aged, Aged, 80 and over, Alleles, Exosomes metabolism, Female, Gene Frequency, Genotype, Glaucoma, Open-Angle metabolism, Glaucoma, Open-Angle physiopathology, Humans, Male, MicroRNAs biosynthesis, Middle Aged, Polymerase Chain Reaction, Aqueous Humor metabolism, Gene Expression Regulation, Genetic Predisposition to Disease, Glaucoma, Open-Angle genetics, Intraocular Pressure physiology, MicroRNAs genetics, RNA genetics
Abstract: Purpose: Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG)., Methods: Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls., Results: Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment., Conclusions: Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.
Published: 2016
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45. ISCB's Initial Reaction to The New England Journal of Medicine Editorial on Data Sharing.

Author: Berger B, Gaasterland T, Lengauer T, Orengo C, Gaeta B, Markel S, and Valencia A
Subjects: New England, Clinical Trials as Topic, Editorial Policies, Information Dissemination, Periodicals as Topic
Published: 2016
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46. ISCB's initial reaction to New England Journal of Medicine editorial on data sharing.

Author: Valencia A, Markel S, Gaeta B, Gaasterland T, Lengauer T, Berger B, and Orengo C
Abstract: This message is a response from the ISCB in light of the recent the New England Journal of Medicine (NEJM) editorial around data sharing.
Published: 2016
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47. PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.

Author: Dickey AS, Pineda VV, Tsunemi T, Liu PP, Miranda HC, Gilmore-Hall SK, Lomas N, Sampat KR, Buttgereit A, Torres MJ, Flores AL, Arreola M, Arbez N, Akimov SS, Gaasterland T, Lazarowski ER, Ross CA, Yeo GW, Sopher BL, Magnuson GK, Pinkerton AB, Masliah E, and La Spada AR
Subjects: Animals, Cell Death drug effects, Chromatin Immunoprecipitation, Disease Models, Animal, Gene Expression Profiling, HEK293 Cells, Humans, Huntingtin Protein, Huntington Disease metabolism, In Vitro Techniques, Induced Pluripotent Stem Cells, Mice, Mice, Transgenic, Mitochondria drug effects, Mitochondria metabolism, Movement drug effects, Nerve Tissue Proteins metabolism, Neurons drug effects, PPAR delta genetics, PPAR delta metabolism, Piperazines pharmacology, Real-Time Polymerase Chain Reaction, Receptors, Cytoplasmic and Nuclear agonists, Sulfonamides pharmacology, Huntington Disease genetics, Neostriatum metabolism, Nerve Tissue Proteins genetics, Neurons metabolism, Receptors, Cytoplasmic and Nuclear genetics
Abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.
Published: 2016
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48. Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells.

Author: Kumar N, Richter J, Cutts J, Bush KT, Trujillo C, Nigam SK, Gaasterland T, Brafman D, and Willert K
Subjects: Cell Culture Techniques, Humans, Tissue Engineering, Cell Differentiation, Mesoderm, Pluripotent Stem Cells physiology, Stem Cells physiology
Abstract: The field of tissue engineering entered a new era with the development of human pluripotent stem cells (hPSCs), which are capable of unlimited expansion whilst retaining the potential to differentiate into all mature cell populations. However, these cells harbor significant risks, including tumor formation upon transplantation. One way to mitigate this risk is to develop expandable progenitor cell populations with restricted differentiation potential. Here, we used a cellular microarray technology to identify a defined and optimized culture condition that supports the derivation and propagation of a cell population with mesodermal properties. This cell population, referred to as intermediate mesodermal progenitor (IMP) cells, is capable of unlimited expansion, lacks tumor formation potential, and, upon appropriate stimulation, readily acquires properties of a sub-population of kidney cells. Interestingly, IMP cells fail to differentiate into other mesodermally-derived tissues, including blood and heart, suggesting that these cells are restricted to an intermediate mesodermal fate.
Published: 2015
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49. Endogenous WNT signaling regulates hPSC-derived neural progenitor cell heterogeneity and specifies their regional identity.

Author: Moya N, Cutts J, Gaasterland T, Willert K, and Brafman DA
Subjects: Biomarkers, Cluster Analysis, Gene Expression Profiling, Humans, Immunophenotyping, Phenotype, Cell Differentiation, Neural Stem Cells cytology, Neural Stem Cells metabolism, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism, Wnt Signaling Pathway
Abstract: Neural progenitor cells (NPCs) derived from human pluripotent stem cells (hPSCs) are a multipotent cell population that is capable of nearly indefinite expansion and subsequent differentiation into the various neuronal and supporting cell types that comprise the CNS. However, current protocols for differentiating NPCs toward neuronal lineages result in a mixture of neurons from various regions of the CNS. In this study, we determined that endogenous WNT signaling is a primary contributor to the heterogeneity observed in NPC cultures and neuronal differentiation. Furthermore, exogenous manipulation of WNT signaling during neural differentiation, through either activation or inhibition, reduces this heterogeneity in NPC cultures, thereby promoting the formation of regionally homogeneous NPC and neuronal cultures. The ability to manipulate WNT signaling to generate regionally specific NPCs and neurons will be useful for studying human neural development and will greatly enhance the translational potential of hPSCs for neural-related therapies., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2014
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50. Let-7 coordinately suppresses components of the amino acid sensing pathway to repress mTORC1 and induce autophagy.

Author: Dubinsky AN, Dastidar SG, Hsu CL, Zahra R, Djakovic SN, Duarte S, Esau CC, Spencer B, Ashe TD, Fischer KM, MacKenna DA, Sopher BL, Masliah E, Gaasterland T, Chau BN, Pereira de Almeida L, Morrison BE, and La Spada AR
Subjects: Adipose Tissue, White metabolism, Animals, Base Sequence, Brain metabolism, Cells, Cultured, HEK293 Cells, Humans, Insulin metabolism, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs antagonists & inhibitors, Monomeric GTP-Binding Proteins antagonists & inhibitors, Monomeric GTP-Binding Proteins genetics, Monomeric GTP-Binding Proteins metabolism, Muscle, Skeletal metabolism, Neurons cytology, Neurons metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, RNA Interference, Sequence Alignment, Signal Transduction, Amino Acids metabolism, Autophagy, MicroRNAs metabolism, Multiprotein Complexes metabolism, TOR Serine-Threonine Kinases metabolism
Abstract: Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway-the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately downregulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms., (Copyright © 2014 Elsevier Inc. All rights reserved.)
Published: 2014
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