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5. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease

Author

Sidransky, E., Nalls, M.A., Aasly, J.O., Aharon-Peretz, J., Annesi, G., Barbosa, E.R., Bar-Shira, A., Berg, D., Bras, J., Brice, A., C.-M. Chen, Clark, L.N., Condroyer, C., De Marco, E.V., Eblan, M.J., Fahn, S., Farrer, M.J., Durr, A., H.-C. Fung, Gan-Or, Z., Gasser, T., Gershoni-Baruch R., Giladi, N., Griffith, A., Gurevich, T., Januario, C., Kropp, P., Lang, A.E., C.-J. Lee Chen, Lesage, S., Marder, K., Mata, I.F., Mirelman, A., Mutsui, J., Mizuta, I., Nicoletti, G., Oliveira, C., Ottman, R., Orr-Urteger, A., Pereira, L.V., Quattron, A., Spitz, M., E.-K. Tan, Tayebi, N., Toda, T., Troiano, S., Tsuji, S., Wittstock, M., Wolfsberg, T.G., Y.-R. Wu, Zabetian, C.P., Y. Zhao, and Ziegler, S.G.

Subjects
Parkinson's disease -- Risk factors, Hydrolases -- Health aspects, Enzymes -- Health aspects
Abstract

The study determines the frequency of glucocerebrosidase ("GBA") mutations in an ethnically diverse group of patients with Parkinson's disease. Findings indicate a strong relation between "GBA" mutations and Parkinson's disease.

Published
2009

23. Serum iron levels and the risk of Parkinson Disease: a Mendelian randomization study

Author

Pichler I, Del Greco M. F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, PD GWAS Consortium, Nalls M, Keller MF, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Benyamin B, Whitfield JB, Genetics of Iron Status Consortium, Pramstaller PP, Hicks AA, Thompson JR, Minelli C., Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón Sánchez J, Schulte C, Lesage S, Arepalli S, Barker R, Ben Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RM, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Charlesworth G, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Dürr A, Edkins S, Evans JR, Foltynie T, Gao J, Gardner M, Gibbs JR, Goate A, Gray E, Guerreiro R, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Huber H, Hudson G, Hunt SE, Illig T, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Sidransky E, Smith C, Spencer CC, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori Ghanbaria A, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams Gray CH, Winder Rhodes S, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson R, Su Z, Vukcevic D, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, McCarthy MI, Ouwehand WH, Radhakrishnan A, Sambrook J, Toniolo D, Camaschella C, Metspalu A, Esko T, Gieger C, Ried J, Meitinger T, Oexle K, Winkelmann J, Swinkels D, Vermeulen S, van Duijn C, Broer L, Beilby J, Hui J, Anderson D, Visscher P, Martin N., TRAGLIA, MICHELA, Pichler, Irene, Del Greco M, Fabiola, Gögele, Martin, Lill, Christina M, Benyamin, Beben, Minelli, Cosetta, PD GWAS Consortium, International Parkinson’s Disease Genomics Consortium, Wellcome Trust Case Control Consortium, Genetics of Iron Status Consortium, Pollak, Pierre, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Human genetics, NCA - Brain mechanisms in health and disease, ANS - Amsterdam Neuroscience, Neurology, Graduate School, Pichler, I, Del Greco M., F, Gögele, M, Lill, Cm, Bertram, L, Do, Cb, Eriksson, N, Foroud, T, Myers, Rh, PD GWAS, Consortium, Nalls, M, Keller, Mf, International Parkinson's Disease Genomics, Consortium, Wellcome Trust Case Control Consortium, 2, Benyamin, B, Whitfield, Jb, Genetics of Iron Status, Consortium, Pramstaller, Pp, Hicks, Aa, Thompson, Jr, Minelli, C., Plagnol, V, Hernandez, Dg, Sharma, M, Sheerin, Um, Saad, M, Simón Sánchez, J, Schulte, C, Lesage, S, Arepalli, S, Barker, R, Ben Shlomo, Y, Berendse, Hw, Berg, D, Bhatia, K, de Bie, Rm, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Bras, Jm, Brockmann, K, Brooks, J, Burn, Dj, Charlesworth, G, Chen, H, Chinnery, Pf, Chong, S, Clarke, Ce, Cookson, Mr, Cooper, Jm, Corvol, Jc, Counsell, C, Damier, P, Dartigues, Jf, Deloukas, P, Deuschl, G, Dexter, Dt, van Dijk, Kd, Dillman, A, Durif, F, Dürr, A, Edkins, S, Evans, Jr, Foltynie, T, Gao, J, Gardner, M, Gibbs, Jr, Goate, A, Gray, E, Guerreiro, R, Harris, C, van Hilten, Jj, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Huber, H, Hudson, G, Hunt, Se, Illig, T, Lambert, Jc, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, Mcneill, A, Moorby, C, Moore, M, Morris, Hr, Morrison, Ke, Mudanohwo, E, O'Sullivan, S, Pearson, J, Perlmutter, J, Pollak, P, Post, B, Potter, S, Ravina, B, Revesz, T, Riess, O, Rivadeneira, F, Rizzu, P, Ryten, M, Sawcer, S, Schapira, A, Scheffer, H, Shaw, K, Shoulson, I, Sidransky, E, Smith, C, Spencer, Cc, Stockton, Jd, Strange, A, Talbot, K, Tanner, Cm, Tashakkori Ghanbaria, A, Trabzuni, D, Traynor, Bj, Uitterlinden, Ag, Velseboer, D, Vidailhet, M, Walker, R, van de Warrenburg, B, Wickremaratchi, M, Williams, N, Williams Gray, Ch, Winder Rhodes, S, Martinez, M, Hardy, J, Heutink, P, Brice, A, Gasser, T, Singleton, Ab, Wood, Nw, Donnelly, P, Barroso, I, Blackwell, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Su, Z, Vukcevic, D, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Ouwehand, Wh, Radhakrishnan, A, Sambrook, J, Toniolo, D, Traglia, Michela, Camaschella, C, Metspalu, A, Esko, T, Gieger, C, Ried, J, Meitinger, T, Oexle, K, Winkelmann, J, Swinkels, D, Vermeulen, S, van Duijn, C, Broer, L, Beilby, J, Hui, J, Anderson, D, Visscher, P, and Martin, N.

Subjects
Relative risk reduction, Iron, Mendelian randomization analysis, Physiology, Genome-wide association study, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, SDG 17 - Partnerships for the Goals, Risk Factors, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Iron/blood, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Parkinson Disease/blood/genetics, Confounding, Parkinson Disease, Mendelian Randomization Analysis, General Medicine, Iron metabolism, 3. Good health, ddc:616.8, Parkinson disease, Meta-analysis, Hereditary hemochromatosis, Serum iron, Medicine, 030217 neurology & neurosurgery, Research Article
Abstract

In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary, Background Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Conclusions Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary, Editors' Summary Background Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease. Why Was This Study Done? Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial. What Did the Researchers Do and Find? The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime. What Do These Findings Mean? These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462. The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Published
2013

24. Castellanos replies

Author

Castellanos, F X, Lau, E, Tayebi, N, Lee, P, Long, R E, Giedd, J N, Sharp, W S, Marsh, W L, Walter, J M, Hamburger, S D, Ginns, E I, Rapoport, J L, and Sidransky, E

Published
1999
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25. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Author

Nalls, M.A. Pankratz, N. Lill, C.M. Do, C.B. Hernandez, D.G. Saad, M. Destefano, A.L. Kara, E. Bras, J. Sharma, M. Schulte, C. Keller, M.F. Arepalli, S. Letson, C. Edsall, C. Stefansson, H. Liu, X. Pliner, H. Lee, J.H. Cheng, R. Ikram, M.A. Ioannidis, J.P.A. Hadjigeorgiou, G.M. Bis, J.C. Martinez, M. Perlmutter, J.S. Goate, A. Marder, K. Fiske, B. Sutherland, M. Xiromerisiou, G. Myers, R.H. Clark, L.N. Stefansson, K. Hardy, J.A. Heutink, P. Chen, H. Wood, N.W. Houlden, H. Payami, H. Brice, A. Scott, W.K. Gasser, T. Bertram, L. Eriksson, N. Foroud, T. Singleton, A.B. Plagnol, V. Sheerin, U.-M. Simón-Sánchez, J. Lesage, S. Sveinbjörnsdóttir, S. Barker, R. Ben-Shlomo, Y. Berendse, H.W. Berg, D. Bhatia, K. de Bie, R.M.A. Biffi, A. Bloem, B. Bochdanovits, Z. Bonin, M. Bras, J.M. Brockmann, K. Brooks, J. Burn, D.J. Charlesworth, G. Chinnery, P.F. Chong, S. Clarke, C.E. Cookson, M.R. Cooper, J.M. Corvol, J.C. Counsell, C. Damier, P. Dartigues, J.-F. Deloukas, P. Deuschl, G. Dexter, D.T. van Dijk, K.D. Dillman, A. Durif, F. Dürr, A. Edkins, S. Evans, J.R. Foltynie, T. Dong, J. Gardner, M. Gibbs, J.R. Gray, E. Guerreiro, R. Harris, C. van Hilten, J.J. Hofman, A. Hollenbeck, A. Holton, J. Hu, M. Huang, X. Wurster, I. Mätzler, W. Hudson, G. Hunt, S.E. Huttenlocher, J. Illig, T. Jónsson, P.V. Lambert, J.-C. Langford, C. Lees, A. Lichtner, P. Limousin, P. Lopez, G. Lorenz, D. McNeill, A. Moorby, C. Moore, M. Morris, H.R. Morrison, K.E. Mudanohwo, E. O’sullivan, S.S. Pearson, J. Pétursson, H. Pollak, P. Post, B. Potter, S. Ravina, B. Revesz, T. Riess, O. Rivadeneira, F. Rizzu, P. Ryten, M. Sawcer, S. Schapira, A. Scheffer, H. Shaw, K. Shoulson, I. Sidransky, E. Smith, C. Spencer, C.C.A. Stefánsson, H. Bettella, F. Stockton, J.D. Strange, A. Talbot, K. Tanner, C.M. Tashakkori-Ghanbaria, A. Tison, F. Trabzuni, D. Traynor, B.J. Uitterlinden, A.G. Velseboer, D. Vidailhet, M. Walker, R. van de Warrenburg, B. Wickremaratchi, M. Williams, N. Williams-Gray, C.H. Winder-Rhodes, S. Stefánsson, K. Hardy, J. Factor, S. Higgins, D. Evans, S. Shill, H. Stacy, M. Danielson, J. Marlor, L. Williamson, K. Jankovic, J. Hunter, C. Simon, D. Ryan, P. Scollins, L. Saunders-Pullman, R. Boyar, K. Costan-Toth, C. Ohmann, E. Sudarsky, L. Joubert, C. Friedman, J. Chou, K. Fernandez, H. Lannon, M. Galvez-Jimenez, N. Podichetty, A. Thompson, K. Lewitt, P. Deangelis, M. O'brien, C. Seeberger, L. Dingmann, C. Judd, D. Marder, K. Fraser, J. Harris, J. Bertoni, J. Peterson, C. Rezak, M. Medalle, G. Chouinard, S. Panisset, M. Hall, J. Poiffaut, H. Calabrese, V. Roberge, P. Wojcieszek, J. Belden, J. Jennings, D. Marek, K. Mendick, S. Reich, S. Dunlop, B. Jog, M. Horn, C. Uitti, R. Turk, M. Ajax, T. Mannetter, J. Sethi, K. Carpenter, J. Dill, B. Hatch, L. Ligon, K. Narayan, S. Blindauer, K. Abou-Samra, K. Petit, J. Elmer, L. Aiken, E. Davis, K. Schell, C. Wilson, S. Velickovic, M. Koller, W. Phipps, S. Feigin, A. Gordon, M. Hamann, J. Licari, E. Marotta-Kollarus, M. Shannon, B. Winnick, R. Simuni, T. Videnovic, A. Kaczmarek, A. Williams, K. Wolff, M. Rao, J. Cook, M. Fernandez, M. Kostyk, S. Hubble, J. Campbell, A. Reider, C. Seward, A. Camicioli, R. Carter, J. Nutt, J. Andrews, P. Morehouse, S. Stone, C. Mendis, T. Grimes, D. Alcorn-Costa, C. Gray, P. Haas, K. Vendette, J. Sutton, J. Hutchinson, B. Young, J. Rajput, A. Klassen, L. Shirley, T. Manyam, B. Simpson, P. Whetteckey, J. Wulbrecht, B. Truong, D. Pathak, M. Frei, K. Luong, N. Tra, T. Tran, A. Vo, J. Lang, A. Kleiner-Fisman, G. Nieves, A. Johnston, L. So, J. Podskalny, G. Giffin, L. Atchison, P. Allen, C. Martin, W. Wieler, M. Suchowersky, O. Furtado, S. Klimek, M. Hermanowicz, N. Niswonger, S. Shults, C. Fontaine, D. Aminoff, M. Christine, C. Diminno, M. Hevezi, J. Dalvi, A. Kang, U. Richman, J. Uy, S. Sahay, A. Gartner, M. Schwieterman, D. Hall, D. Leehey, M. Culver, S. Derian, T. Demarcaida, T. Thurlow, S. Rodnitzky, R. Dobson, J. Lyons, K. Pahwa, R. Gales, T. Thomas, S. Shulman, L. Weiner, W. Dustin, K. Singer, C. Zelaya, L. Tuite, P. Hagen, V. Rolandelli, S. Schacherer, R. Kosowicz, J. Gordon, P. Werner, J. Serrano, C. Roque, S. Kurlan, R. Berry, D. Gardiner, I. Hauser, R. Sanchez-Ramos, J. Zesiewicz, T. Delgado, H. Price, K. Rodriguez, P. Wolfrath, S. Pfeiffer, R. Davis, L. Pfeiffer, B. Dewey, R. Hayward, B. Johnson, A. Meacham, M. Estes, B. Walker, F. Hunt, V. O'neill, C. Racette, B. Swisher, L. Dijamco, C. Conley, E.D. Dorfman, E. Tung, J.Y. Hinds, D.A. Mountain, J.L. Wojcicki, A. Lew, M. Klein, C. Golbe, L. Growdon, J. Wooten, G.F. Watts, R. Guttman, M. Goldwurm, S. Saint-Hilaire, M.H. Baker, K. Litvan, I. Nicholson, G. Nance, M. Drasby, E. Isaacson, S. Burn, D. Pramstaller, P. Al-Hinti, J. Moller, A. Sherman, S. Roxburgh, R. Slevin, J. Perlmutter, J. Mark, M.H. Huggins, N. Pezzoli, G. Massood, T. Itin, I. Corbett, A. Chinnery, P. Ostergaard, K. Snow, B. Cambi, F. Kay, D. Samii, A. Agarwal, P. Roberts, J.W. Higgins, D.S. Molho, E. Rosen, A. Montimurro, J. Martinez, E. Griffith, A. Kusel, V. Yearout, D. Factor, S. Zabetian, C. Clark, L.N. Liu, X. Lee, J.H. Cheng Taub, R. Louis, E.D. Cote, L.J. Waters, C. Ford, B. Fahn, S. Vance, J.M. Beecham, G.W. Martin, E.R. Nuytemans, K. Pericak-Vance, M.A. Haines, J.L. Destefano, A. Seshadri, S. Choi, S.H. Frank, S. Bis, J.C. Psaty, B.M. Rice, K. Longstreth, W.T., Jr. Ton, T.G.N. Jain, S. van Duijn, C.M. Uitterlinden, A.G. Verlinden, V.J. Koudstaal, P.J. Singleton, A. Cookson, M. Gibbs, J.R. Hernandez, D. Nalls, M. Zonderman, A. Ferrucci, L. Johnson, R. Longo, D. O'brien, R. Traynor, B. Troncoso, J. van der Brug, M. Zielke, R. Weale, M. Ramasamy, A. Dardiotis, E. Tsimourtou, V. Spanaki, C. Plaitakis, A. Bozi, M. Stefanis, L. Vassilatis, D. Koutsis, G. Panas, M. Hadjigeorgiou, G.M. Lunnon, K. Lupton, M. Powell, J. Parkkinen, L. Ansorge, O. International Parkinson's Disease Genomics Consortium (IPDGC) Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI) 23andMe GenePD NeuroGenetics Research Consortium (NGRC) Hussman Institute of Human Genomics (HIHG) The Ashkenazi Jewish Dataset Investigator Cohorts for Health Aging Research in Genetic Epidemiology (CHARGE) North American Brain Expression Consortium (NABEC) United Kingdom Brain Expression Consortium (UKBEC) Greek Parkinson's Disease Consortium Alzheimer Genetic Analysis Group

Abstract

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation. © 2014 Nature America, Inc. All rights reserved.

Published
2014

27. The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism

Author

DePaolo, J., Goker-Alpan, O., Samaddar, T., Lopez, G., and Sidransky, E.

Subjects
Adult, Lewy Body Disease, Male, Gaucher Disease, DNA Mutational Analysis, Genetic Counseling, Middle Aged, Hippocampus, Article, nervous system diseases, Substantia Nigra, Parkinsonian Disorders, Risk Factors, Mutation, Ethnicity, alpha-Synuclein, Glucosylceramidase, Humans, Enzyme Replacement Therapy, Female, Genetic Predisposition to Disease, Child, Lysosomes, Aged
Abstract

A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase (GBA), the gene implicated in Gaucher disease, and the development of parkinsonism. Several different lines of research support this relationship. First, patients with Gaucher disease who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with Gaucher disease have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with Parkinson disease as well as other Lewy body disorders have at least a five–fold increase in the number of carriers of GBA mutations as compared to age matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra and involvement of hippocampal layers CA2−4. While the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a Parkinson risk factor across different centers, synucleinopathies and ethnicities. Further studies of the association between Gaucher disease and parkinsonism will stimulate new insights into the pathophysisology of the two disorders, and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism.

Published
2009

28. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease

Author

Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, and Griff

Abstract

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease

Published
2009

33. Transvaginal chorionic villus sampling.

Author

Sidransky, Ellen, Black, Susan H., Soenksen, Dawn M., Jones, Shirley L., Dorfmann, Andrew D., Schulman, Joseph D., Sidransky, E, Black, S H, Soenksen, D M, Jones, S L, Dorfmann, A D, and Schulman, J D

Published
1990
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34. The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease.

Author

Sidransky, E, Tayebi, N, Stubblefield, B K, Eliason, W, Klineburgess, A, Pizzolato, G P, Cox, J N, Porta, J, Bottani, A, and DeLozier-Blanchet, C D

Abstract

It has recently been emphasised that a subset of patients with type 2 Gaucher disease die in the neonatal period. This report describes an Afghani family with two conceptuses having severe, prenatally detected Gaucher disease. Mutational analysis showed that the family carried a known complex allele which included mutations at amino acids L444P, A456P, and V460V. Although glucocerebrosidase RNA was present, an affected fetus had virtually no glucocerebrosidase cross reactive material on western analyses. The severe clinical course and pathology observed in these patients resemble that of the null allele Gaucher mouse, and suggest that the absence of glucocerebrosidase activity results in early death. [ABSTRACT FROM PUBLISHER]

Published
1996

36. Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/ hyperactivity disorder: genetic and brain morphometric analyses.

Author

Castellanos, F.X., Lau, E., Tayebi, N., Lee, P., Long, R.E., Giedd, J.N., Sharp, W., Marsh, W.L., Walter, J.M., Hamburger, S.D., Ginns, E.I., Rapoport, J.L., and Sidransky, E.

Subjects
DOPAMINE receptors, ATTENTION-deficit hyperactivity disorder
Abstract

Studies the association between dopamine-4 receptor polymorphisms and attention-deficit hyperactivity disorder (ADHD) in children. Difference in the frequency of dopamine-4 receptor alleles in ADHD between patients and psychiatrically screened controls; Comparison of behavioral measures and anatomic brain morphometry between the control groups.

Published
1998
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45. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?

Author

Tayebi, N., Walker, J., Stubblefield, B., Orvisky, E., LaMarca, M.E., Wong, K., Rosenbaum, H., Schiffmann, R., Bembi, B., and Sidransky, E.

Subjects
*GAUCHER'S disease, *PARKINSON'S disease
Abstract

Among the phenotypes associated with Gaucher disease, the deficiency of glucocerebrosidase, are rare patients with early onset, treatment-refractory parkinsonism. Sequencing of glucocerebrosidase in 17 such patients revealed 12 different genotypes. Fourteen patients had the common “non-neuronopathic” N370S mutation, including five N370S homozygotes. While brain glucosylsphingosine levels were not elevated, Lewy bodies were seen in the four brains available for study. The shared clinical and neuropathologic findings in this subgroup suggest that the deficiency in glucocerebrosidase may contribute to a vulnerability to parkinsonism. [Copyright &y& Elsevier]

Published
2003
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48. High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.

Author

Williams D, Glasstetter LM, Jong TT, Chen T, Kapoor A, Zhu S, Zhu Y, Calvo R, Gehrlein A, Wong K, Hogan AN, Vocadlo DJ, Jagasia R, Marugan JJ, Sidransky E, Henderson MJ, and Chen Y

Subjects
Humans, Small Molecule Libraries pharmacology, Cell Line, Tumor, Glucosylceramidase metabolism, Glucosylceramidase genetics, Gaucher Disease drug therapy, Gaucher Disease genetics, Gaucher Disease metabolism, Parkinson Disease drug therapy, Parkinson Disease metabolism, Parkinson Disease genetics, High-Throughput Screening Assays methods, Protein Folding drug effects
Abstract

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT- GBA1 transgene into an intragenic safe-harbor locus in GBA1 -knockout H4 (neuroglioma) cells. This GD cell model was amenable to lead discovery via titration-based quantitative high-throughput screening and lead optimization via structure-activity relationships. A primary screen of 10,779 compounds from the NCATS bioactive collections identified 140 stabilizers of HiBiT-GCase-L444P, including both pharmacological chaperones (ambroxol and noninhibitory chaperone NCGC326) and proteostasis regulators (panobinostat, trans-ISRIB, and pladienolide B). Two complementary high-content imaging-based assays were deployed to triage hits: The fluorescence-quenched substrate LysoFix-GBA captured functional lysosomal GCase activity, while an immunofluorescence assay featuring antibody hGCase-1/23 directly visualized GCase lysosomal translocation. NCGC326 was active in both secondary assays and completely reversed pathological glucosylsphingosine accumulation. Finally, we tested the concept of combination therapy by demonstrating synergistic actions of NCGC326 with proteostasis regulators in enhancing GCase-L444P levels. Looking forward, these physiologically relevant assays can facilitate the identification, pharmacological validation, and medicinal chemistry optimization of small molecules targeting GCase, ultimately leading to a viable therapeutic for GD and PD., Competing Interests: Competing interests statement:A.G. and R.J. are employees of F. Hoffmann-La Roche AG.

Published
2024
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49. Consensus Guidance for Genetic Counseling in GBA1 Variants: A Focus on Parkinson's Disease.

Author

Vieira SRL, Mezabrovschi R, Toffoli M, Del Pozo SL, Menozzi E, Mullin S, Yalkic S, Limbachiya N, Koletsi S, Loefflad N, Lopez GJ, Gan-Or Z, Alcalay RN, Sidransky E, and Schapira AHV

Abstract

Glucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving. We review the current knowledge of the link between GBA1 and PD, and discuss the practicalities of GBA1 testing. Lastly, we provide a consensus for an approach to counseling people with GBA1 variants, notably the communication of PD risk. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Published
2024
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50. Gaucher disease provides a unique window into Parkinson disease pathogenesis.

Author

Hertz E, Chen Y, and Sidransky E

Subjects
Humans, Animals, Mutation genetics, Gaucher Disease genetics, Parkinson Disease genetics, Glucosylceramidase genetics
Abstract

An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous for Gaucher GBA1 mutations, and 3-25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD., (© 2024. Springer Nature Limited.)

Published
2024
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