Background: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods: We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings: Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10-8DHFR p=8·37 × 10-7 MTRNR2L2 p=2·15 × 10-9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10-4DHFR p=8·45 × 10-4MTRNR2L2 p=1·20 × 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16-0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06-0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation: The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding: The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study / J Hensman Moss, Davina; F Pardiñas, Antonio; Langbehn, Douglas; Lo, Kitty; R Leavitt, Blair; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; J Tabrizi, Sarah; Coleman, A; Dar Santos, R; Decolongon, J; Sturrock, A; Bardinet, E; Jauff Ret, C; Justo, D; Lehericy, S; Marelli, C; Nigaud, K; Valabrègue, R; van den Bogaard, Sja; M Dumas, E; van der Grond, J; T'Hart, Ep; Jurgens, C; Witjes-Ane, M-N; Arran, N; Callaghan, J; Stopford, C; Frost, C; Jones, R; Hobbs, N; Lahiri, N; Ordidge, R; Owen, G; Pepple, T; Read, J; Say, M; Wild, E; Patel, A; C Fox, N; Gibbard, C; Malone, I; Crawford, H; Whitehead, D; Keenan, S; M Cash, D; Berna, C; Bechtel, N; Bohlen, S; Hoff Man, A; Kraus, P; Axelson, E; Wang, C; Acharya, T; Lee, S; Monaco, W; Campbell, C; Queller, S; Whitlock, K; Campbell, C; Campbell, M; Frajman, E; Milchman, C; O'Regan, A; Labuschagne, I; Stout, J; Landwehrmeyer, B; Craufurd, D; Scahill, R; Hicks, S; Kennard, C; Johnson, H; Tobin, A; Rosas, Hd; Reilmann, R; Borowsky, B; Pourchot, C; C Andrews, S; Bachoud-Lévi, Anne-Catherine; Rita Bentivoglio, Anna; Biunno, Ida; Bonelli, Raphael; Burgunder, Jean-Marc; Dunnett, Stephen; Ferreira, Joaquim; Handley, Olivia; Heiberg, Arvid; Illmann, Torsten; Bernhard Landwehrmeyer, G.; Levey, Jamie; Ramos-Arroyo, Maria A.; Nielsen, Jørgen; Pro Koivisto, Susana; Päivärinta, Markku; Roos, Raymund A. C.; Rojo Sebastián, A; Tabrizi, Sarah; Vandenberghe, Wim; Verellen-Dumoulin, Christine; Uhrova, Tereza; Wahlström, Jan; Zaremba, Jacek; Baake, Verena; Barth, Katrin; Bascuñana Garde, Monica; Betz, Sabrina; Bos, Reineke; Callaghan, Jenny; Come, Adrien; Correia Guedes, Leonor; Ecker, Daniel; Maria Finisterra, Ana; Fullam, Ruth; Gilling, Mette; Gustafsson, Lena; J Handley, Olivia; Hvalstedt, Carina; Held, Christine; Koppers, Kerstin; Lamanna, Claudia; Laurà, Matilde; Martínez Descals, Asunción; Martinez-Horta, Saül; Mestre, Tiago; Minster, Sara; Monza, Daniela; Mütze, Lisanne; Oehmen, Martin; Orth, Michael; Padieu, Hélène; Paterski, Laurent; Peppa, Nadia; Pro Koivisto, Susana; Di Renzo, Martina; Rialland, Amandine; Røren, Niini; Šašinková, Pavla; Timewell, Erika; Townhill, Jenny; Trigo Cubillo, Patricia; Vieira da Silva, Wildson; R van Walsem, Marleen; Whalstedt, Carina; Witjes-Ané, Marie-Noelle; Witkowski, Grzegorz; Wright, Abigail; Zielonka, Daniel; Zielonka, Eugeniusz; Zinzi, Paola; Bonelli, Raphael M.; Lilek, Sabine; Hecht, Karen; Herranhof, Brigitte; Holl, Anna; Kapfhammer, Hans-Peter; Koppitz, Michael; Magnet, Markus; Müller, Nicole; Otti, Daniela; Painold, Annamaria; Reisinger, Karin; Scheibl, Monika; Schöggl, Helmut; Ullah, Jasmin; Braunwarth, Eva-Maria; Brugger, Florian; Buratti, Lisa; Hametner, Eva-Maria; Hepperger, Caroline; Holas, Christiane; Hotter, Anna; Hussl, Anna; Müller, Christoph; Poewe, Werner; Seppi, Klaus; Sprenger, Fabienne; Wenning, Gregor; Boogaerts, Andrea; Calmeyn, Godelinde; Delvaux, Isabelle; Liessens, Dirk; Somers, Nele; Dupuit, Michel; Minet, Cécile; van Paemel, Dominique; Ribaï, Pascale; Verellen-Dumoulin, Christine; Boogaerts, Andrea; Vandenberghe, Wim; van Reijen, Dimphna; Klempír, Jirí; Majerová, Veronika; Roth, Jan; Stárková, Irena; Hjermind, Lena E.; Jacobsen, Oda; Nielsen, Jørgen E.; Unmack Larsen, Ida; Vinther-Jensen, Tua; Hiivola, Heli; Hyppönen, Hannele; Martikainen, Kirsti; Tuuha, Katri; Allain, Philippe; Bonneau, Dominique; Bost, Marie; Gohier, Bénédicte; Guérid, Marie-Anne; Olivier, Audrey; Prundean, Adriana; Scherer-Gagou, Clarisse; Verny, Christophe; Babiloni, Blandine; Debruxelles, Sabrina; Duché, Charlotte; Goizet, Cyril; Jameau, Laetitia; Lafoucrière, Danielle; Spampinato, Umberto; Barthélémy, Rekha; De Bruycker, Christelle; Cabaret Anne-Sophie Carette, Maryline; Decorte Luc Defebvre, Eric; Delliaux, Marie; Delval, Arnaud; Destee, Alain; Dujardin, Kathy; Lemaire, Marie-Hélène; Manouvrier, Sylvie; Peter, Mireille; Plomhouse, Lucie; Sablonnière, Bernard; Simonin, Clémence; Thibault-Tanchou, Stéphanie; Vuillaume, Isabelle; Bellonet, Marcellin; Berrissoul, Hassan; Blin, Stéphanie; Courtin, Françoise; Duru, Cécile; Fasquel, Véronique; Godefroy, Olivier; Krystkowiak, Pierre; Mantaux, Béatrice; Roussel, Martine; Wannepain, Sandrine; Azulay, Jean-Philippe; Delfini, Marie; Eusebio, Alexandre; Fluchere, Frédérique; Mundler, Laura; Anheim, Mathieu; Julié, Celine; Lagha Boukbiza, Ouhaid; Longato, Nadine; Rudolf, Gabrielle; Tranchant, Christine; Zimmermann, Marie-Agathe; Michael Kosinski, Christoph; Milkereit, Eva; Probst, Daniela; Reetz, Kathrin; Sass, Christian; Schiefer, Johannes; Schlangen, Christiane; Werner, Cornelius J.; Gelderblom, Harald; Priller, Josef; Prüß, Harald; Jakob Spruth, Eike; Ellrichmann, Gisa; Herrmann, Lennard; Hoffmann, Rainer; Kaminski, Barbara; Kotz, Peter; Prehn, Christian; Saft, Carsten; Lange, Herwig; Maiwald, Robert; Löhle, Matthias; Maass, Antonia; Schmidt, Simone; Bosredon, Cecile; Storch, Alexander; Wolz, Annett; Wolz, Martin; Capetian, Philipp; Lambeck, Johann; Zucker, Birgit; Boelmans, Kai; Ganos, Christos; Heinicke, Walburgis; Hidding, Ute; Lewerenz, Jan; Münchau, Alexander; Orth, Michael; Schmalfeld, Jenny; Stubbe, Lars; Zittel, Simone; Diercks, Gabriele; Dressler, Dirk; Gorzolla, Heike; Schrader, Christoph; Tacik, Pawel; Ribbat, Michael; Longinus, Bernhard; Bürk, Katrin; Carsten Möller, Jens; Rissling, Ida; Mühlau, Mark; Peinemann, Alexander; Städtler, Michael; Weindl, Adolf; Winkelmann, Juliane; Ziegler, Cornelia; Bechtel, Natalie; Beckmann, Heike; Bohlen, Stefan; Hölzner, Eva; Lange, Herwig; Reilmann, Ralf; Rohm, Stefanie; Rumpf, Silke; Schepers, Sigrun; Weber, Natalia; Dose, Matthias; Leythäuser, Gabriele; Marquard, Ralf; Raab, Tina; Wiedemann, Alexandra; Barth, Katrin; Buck, Andrea; Connemann, Julia; Ecker, Daniel; Geitner, Carolin; Held, Christine; Kesse, Andrea; Landwehrmeyer, Bernhard; Lang, Christina; Lewerenz, Jan; Lezius, Franziska; Nepper, Solveig; Niess, Anke; Orth, Michael; Schneider, Ariane; Schwenk, Daniela; Süßmuth, Sigurd; Trautmann, Sonja; Weydt, Patrick; Cormio, Claudia; Sciruicchio, Vittorio; Serpino, Claudia; de Tommaso, Marina; Capellari, Sabina; Cortelli, Pietro; Galassi, Roberto; Rizzo, Giovanni; Poda, Roberto; Scaglione, Cesa; Bertini, Elisabetta; Ghelli, Elena; Ginestroni, Andrea; Massaro, Francesca; Mechi, Claudia; Paganini, Marco; Piacentini, Silvia; Pradella, Silvia; Maria Romoli, Anna; Sorbi, Sandro; Abbruzzese, Giovanni; Bandettini di Poggio, Monica; Ferrandes, Giovanna; Mandich, Paola; Marchese, Roberta; Albanese, Alberto; Di Bella, Daniela; Castaldo, Anna; Di Donato, Stefano; Gellera, Cinzia; Genitrini, Silvia; Mariotti, Caterina; Monza, Daniela; Nanetti, Lorenzo; Paridi, Dominga; Soliveri, Paola; Tomasello, Chiara; De Michele, Giuseppe; Di Maio, Luigi; Massarelli, Marco; Peluso, Silvio; Roca, Alessandro; Valeria Russo, Cinzia; Salvatore, Elena; Sorrentino, Pierpaolo; Amico, Enrico; Favellato, Mariagrazia; Griguoli, Annamaria; Mazzante, Irene; Petrollini, Martina; Squitieri, Ferdinando; D'Alessio, Barbara; Esposito, Chiara; Bentivoglio, Rita; Frontali, Marina; Guidubaldi, Arianna; Ialongo, Tamara; Jacopini, Gioia; Piano, Carla; Romano, Silvia; Soleti, Francesco; Spadaro, Maria; Zinzi, Paola; van Hout, Monique S. E.; Verhoeven, Marloes E.; van Vugt, Jeroen P. P.; Marit de Weert, A.; Bolwijn, J. J. W.; Dekker, M.; Kremer, B.; Leenders, K. L.; van Oostrom, J. C. H.; van den Bogaard, Simon J. A.; Bos, Reineke; Dumas, Eve M.; 't Hart, Ellen P.; Roos, Raymund A. C.; Kremer, Berry; Verstappen, C. C. P.; Aaserud, Olaf; C, Jan Frich; Heiberg, Arvid; R van Walsem, Marleen; Wehus, Ragnhild; Bjørgo, Kathrine; Fannemel, Madeleine; Gørvell, Per F.; Lorentzen, Eirin; Pro Koivisto, Susana; Retterstøl, Lars; Stokke, Bodil; Bjørnevoll, Inga; Botne Sando, Sigrid; Dziadkiewicz, Artur; Nowak, Malgorzata; Robowski, Piotr; Sitek, Emilia; Slawek, Jaroslaw; Soltan, Witold; Szinwelski, Michal; Blaszcyk, Magdalena; Boczarska-Jedynak, Magdalena; Ciach-Wysocka, Ewelina; Gorzkowska, Agnieszka; Jasinska-Myga, Barbara; Klodowska-Duda, Gabriela; Opala, Gregorz; Stompel, Daniel; Banaszkiewicz, Krzysztof; Bocwinska, Dorota; Bojakowska-Jaremek, Kamila; Dec, Malgorzata; Krawczyk, Malgorzata; Rudzinska, Monika; Szczygiel, Elzbieta; Szczudlik, Andrzej; Wasielewska, Anna; Wójcik, Magdalena; Bryl, Anna; Ciesielska, Anna; Klimberg, Aneta; Marcinkowski, Jerzy; Samara, Husam; Sempolowicz, Justyna; Zielonka, Daniel; Gogol, Anna; Janik, Piotr; Kwiecinski, Hubert; Jamrozik, Zygmunt; Antczak, Jakub; Jachinska, Katarzyna; Krysa, Wioletta; Rakowicz, Maryla; Richter, Przemyslaw; Rola, Rafal; Ryglewicz, Danuta; Sienkiewicz-Jarosz, Halina; Stepniak, Iwona; Sulek, Anna; Witkowski, Grzegorz; Zaremba, Jacek; Zdzienicka, Elzbieta; Zieora-Jakutowicz, Karolina; J Ferreira, Joaquim; Coelho, Miguel; Correia Guedes, Leonor; Mendes, Tiago; Mestre, Tiago; Valadas, Anabela; Andrade, Carlos; Gago, Miguel; Garrett, Carolina; Rosália Guerra, Maria; Durán Herrera, Carmen; Moreno Garcia, Patrocinio; Aguilar Barbera, Miquel; Badenes Guia, Dolors; Casas Hernanz, Laura; López Catena, Judit; Quiléz Ferrer, Pilar; Rojo Sebastián, Ana; Tome Carruesco, Gemma; Bas, Jordi; Busquets, Núria; Calopa, Matilde; Floriach Robert, Misericordia; Mareca Viladrich, Celia; Miguel Ruiz Idiago, Jesús; Villa Riballo, Antonio; Cubo, Esther; Gil Polo, Cecilia; Mariscal, Natividad; Jessica Rivadeneyra, Perez; Barrero, Francisco; Morales, Blas; Fenollar, María; García-Ramos García, Rocío; Ortega, Paloma; Villanueva, Clara; Alegre, Javier; Bascuñana, Mónica; Garcia Caldentey, Juan; Fatás Ventura, Marta; García Ribas, Guillermo; García de Yébenes, Justo; Luis López-Sendón Moreno, José; Trigo Cubillo, Patricia; Alegre, Javier; Alonso Frech, Fernando; García de Yébenes, Justo; J García Ruíz, Pedro; Martínez-Descals, Asunción; Guerrero, Rosa; José Saiz Artiga, María; Sánchez, Vicenta; Fuensanta Noguera Perea, María; Fortuna, Lorenza; Manzanares, Salvadora; Reinante, Gema; Martirio Antequera Torres, María; Vivancos Moreau, Laura; González González, Sonia; Menéndez Guisasola, Luis; Salvador, Carlos; Suaréz San Martín, Esther; Legarda Ramirez, Inés; Gorospe, Aranzazú; Rodriguez Lopera, Mónica; Navas Arques, Penelope; José Torres Rodríguez, María; Vives Pastor, Barbara; Gaston, Itziar; Dolores Martinez-Jaurrieta, Maria; Ramos-Arroyo, Maria A.; Manuel Garcia Moreno, Jose; Mendez Lucena, Carolina; Damas, Fatima; Eva Pacheco Cortegana, Hermoso; Chacón Peña, José; Redondo, Luis; Carrillo, Fátima; Teresa Cáceres, María; Mir, Pablo; José Lama Suarez, María; Vargas-González, Laura; Bosca, Maria E.; Castera Brugada, Francisco; Andres Burguera, Juan; Campos, Anabel; Carmen Peiró Vilaplana, Garcia; Berglund, Peter; Constantinescu, Radu; Fredlund, Gunnel; Høsterey-Ugander, Ulrika; Linnsand, Petra; Neleborn-Lingefjärd, Liselotte; Wahlström, Jan; Wentzel, Magnus; Loutfi, Ghada; Olofsson, Carina; Stattin, Eva-Lena; Westman, Laila; Wikström, Birgitta; Burgunder, Jean-Marc; Stebler, Yanik; Kaelin, Alain; Romero, Irene; Schüpbach, Michael; Weber Zaugg, Sabine; Hauer, Maria; Gonzenbach, Roman; Jung, Hans H.; Mihaylova, Violeta; Petersen, Jens; Jack, Roisin; Matheson, Kirsty; Miedzybrodzka, Zosia; Rae, Daniela; A Simpson, Sheila; Summers, Fiona; Ure, Alexandra; Vaughan, Vivien; Akhtar, Shahbana; Crooks, Jenny; Curtis, Adrienne; de Souza, Jenny; Piedad, John; Rickards, Hugh; Wright, Jan; Coulthard, Elizabeth; Gethin, Louise; Hayward, Beverley; Sieradzan, Kasia; Wright, Abigail; Armstrong, Matthew; Barker, Roger A.; O'Keefe, Deidre; Di Pietro, Anna; Fisher, Kate; Goodman, Anna; Hill, Susan; Kershaw, Ann; Mason, Sarah; Paterson, Nicole; Raymond, Lucy; Swain, Rachel; Valle Guzman, Natalie; Busse, Monica; Butcher, Cynthia; Callaghan, Jenny; Dunnett, Stephen; Clenaghan, Catherine; Fullam, Ruth; Handley, Olivia; Hunt, Sarah; Jones, Lesley; Jones, Una; Khalil, Hanan; Minster, Sara; Owen, Michael; Price, Kathleen; Rosser, Anne; Townhill, Jenny; Edwards, Maureen; Ho, Carrie; Hughes, Teresa; Mcgill, Marie; Pearson, Pauline; Porteous, Mary; Smith, Paul; Brockie, Peter; Foster, Jillian; Johns, Nicola; Mckenzie, Sue; Rothery, Jean; Thomas, Gareth; Yates, Shona; Burrows, Liz; Chu, Carol; Fletcher, Amy; Gallantrae, Deena; Hamer, Stephanie; Harding, Alison; Klöppel, Stefan; Kraus, Alison; Laver, Fiona; Lewis, Monica; Longthorpe, Mandy; Markova, Ivana; Raman, Ashok; Robertson, Nicola; Silva, Mark; Thomson, Aileen; Wild, Sue; Yardumian, Pam; Chu, Carol; Evans, Carole; Gallentrae, Deena; Hamer, Stephanie; Kraus, Alison; Markova, Ivana; Raman, Ashok; Chu, Carol; Hamer, Stephanie; Hobson, Emma; Jamieson, Stuart; Kraus, Alison; Markova, Ivana; Raman, Ashok; Musgrave, Hannah; Rowett, Liz; Toscano, Jean; Wild, Sue; Yardumian, Pam; Bourne, Colin; Clapton, Jackie; Clayton, Carole; Dipple, Heather; Freire-Patino, Dawn; Grant, Janet; Gross, Diana; Hallam, Caroline; Middleton, Julia; Murch, Ann; Thompson, Catherine; Alusi, Sundus; Davies, Rhys; Foy, Kevin; Gerrans, Emily; Pate, Louise; Andrews, Thomasin; Dougherty, Andrew; Golding, Charlotte; Kavalier, Fred; Laing, Hana; Lashwood, Alison; Robertson, Dene; Ruddy, Deborah; Santhouse, Alastair; Whaite, Anna; Andrews, Thomasin; Bruno, Stefania; Doherty, Karen; Golding, Charlotte; Haider, Salman; Hensman, Davina; Lahiri, Nayana; Lewis, Monica; Novak, Marianne; Patel, Aakta; Robertson, Nicola; Rosser, Elisabeth; Tabrizi, Sarah; Taylor, Rachel; Warner, Thomas; Wild, Edward; Arran, Natalie; Bek, Judith; Callaghan, Jenny; Craufurd, David; Fullam, Ruth; Hare, Marianne; Howard, Liz; Huson, Susan; Johnson, Liz; Jones, Mary; Murphy, Helen; Oughton, Emma; Partington-Jones, Lucy; Rogers, Dawn; Sollom, Andrea; Snowden, Julie; Stopford, Cheryl; Thompson, Jennifer; Trender-Gerhard, Iris; Verstraelen, Nichola; Westmoreland, Leann; Armstrong, Richard; Dixon, Kathryn; H Nemeth, Andrea; Siuda, Gill; Valentine, Ruth; Harrison, David; Hughes, Max; Parkinson, Andrew; Soltysiak, Beverley; Bandmann, Oliver; Bradbury, Alyson; Gill, Paul; Fairtlough, Helen; Fillingham, Kay; Foustanos, Isabella; Kazoka, Mbombe; O'Donovan, Kirsty; Peppa, Nadia; Taylor, Cat; Tidswell, Katherine; Quarrell, Oliver; Burgunder, Jean-Marc; Ngoh Lau, Puay; Pica, Emmanul; Tan, Louis. - In: LANCET NEUROLOGY. - ISSN 1474-4465. - 16:9(2017). [10.1016/s1474-4422(17)30161-8]

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Pierpaolo Sorrentino;
2017-01-01

Abstract

Background: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods: We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings: Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10-8DHFR p=8·37 × 10-7 MTRNR2L2 p=2·15 × 10-9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10-4DHFR p=8·45 × 10-4MTRNR2L2 p=1·20 × 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16-0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06-0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation: The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding: The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
2017
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study / J Hensman Moss, Davina; F Pardiñas, Antonio; Langbehn, Douglas; Lo, Kitty; R Leavitt, Blair; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; J Tabrizi, Sarah; Coleman, A; Dar Santos, R; Decolongon, J; Sturrock, A; Bardinet, E; Jauff Ret, C; Justo, D; Lehericy, S; Marelli, C; Nigaud, K; Valabrègue, R; van den Bogaard, Sja; M Dumas, E; van der Grond, J; T'Hart, Ep; Jurgens, C; Witjes-Ane, M-N; Arran, N; Callaghan, J; Stopford, C; Frost, C; Jones, R; Hobbs, N; Lahiri, N; Ordidge, R; Owen, G; Pepple, T; Read, J; Say, M; Wild, E; Patel, A; C Fox, N; Gibbard, C; Malone, I; Crawford, H; Whitehead, D; Keenan, S; M Cash, D; Berna, C; Bechtel, N; Bohlen, S; Hoff Man, A; Kraus, P; Axelson, E; Wang, C; Acharya, T; Lee, S; Monaco, W; Campbell, C; Queller, S; Whitlock, K; Campbell, C; Campbell, M; Frajman, E; Milchman, C; O'Regan, A; Labuschagne, I; Stout, J; Landwehrmeyer, B; Craufurd, D; Scahill, R; Hicks, S; Kennard, C; Johnson, H; Tobin, A; Rosas, Hd; Reilmann, R; Borowsky, B; Pourchot, C; C Andrews, S; Bachoud-Lévi, Anne-Catherine; Rita Bentivoglio, Anna; Biunno, Ida; Bonelli, Raphael; Burgunder, Jean-Marc; Dunnett, Stephen; Ferreira, Joaquim; Handley, Olivia; Heiberg, Arvid; Illmann, Torsten; Bernhard Landwehrmeyer, G.; Levey, Jamie; Ramos-Arroyo, Maria A.; Nielsen, Jørgen; Pro Koivisto, Susana; Päivärinta, Markku; Roos, Raymund A. C.; Rojo Sebastián, A; Tabrizi, Sarah; Vandenberghe, Wim; Verellen-Dumoulin, Christine; Uhrova, Tereza; Wahlström, Jan; Zaremba, Jacek; Baake, Verena; Barth, Katrin; Bascuñana Garde, Monica; Betz, Sabrina; Bos, Reineke; Callaghan, Jenny; Come, Adrien; Correia Guedes, Leonor; Ecker, Daniel; Maria Finisterra, Ana; Fullam, Ruth; Gilling, Mette; Gustafsson, Lena; J Handley, Olivia; Hvalstedt, Carina; Held, Christine; Koppers, Kerstin; Lamanna, Claudia; Laurà, Matilde; Martínez Descals, Asunción; Martinez-Horta, Saül; Mestre, Tiago; Minster, Sara; Monza, Daniela; Mütze, Lisanne; Oehmen, Martin; Orth, Michael; Padieu, Hélène; Paterski, Laurent; Peppa, Nadia; Pro Koivisto, Susana; Di Renzo, Martina; Rialland, Amandine; Røren, Niini; Šašinková, Pavla; Timewell, Erika; Townhill, Jenny; Trigo Cubillo, Patricia; Vieira da Silva, Wildson; R van Walsem, Marleen; Whalstedt, Carina; Witjes-Ané, Marie-Noelle; Witkowski, Grzegorz; Wright, Abigail; Zielonka, Daniel; Zielonka, Eugeniusz; Zinzi, Paola; Bonelli, Raphael M.; 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[10.1016/s1474-4422(17)30161-8]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/343089
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