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

Hensman Moss, Davina J., Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Langbehn, Douglas, Lo, Kitty, Leavitt, Blair R., Roos, Raymund, Durr, Alexandra, Mead, Simon, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Jones, Lesley ORCID: https://orcid.org/0000-0001-7156-8531, Tabrizi, Sarah J., Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrègue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., t'Hart, E. P., Jurgens, C., Witjes-Ane, M.-N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R. ORCID: https://orcid.org/0000-0001-7156-8531, Hobbs, N., Lahiri, N., Ordidge, R., Owen, G. ORCID: https://orcid.org/0000-0003-4798-0862, Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A . Hoff, 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, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-Lévi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen ORCID: https://orcid.org/0000-0003-1826-1578, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jørgen, Koivisto, Susana Pro, Päivärinta, Markku, Roos, Raymund A.C., Sebastián, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlström, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica Bascuñana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J., Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mütze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hélène, Paterski, Laurent, Peppa, Nadia, Koivisto, Susana Pro, Di Renzo, Martina, Rialland, Amandine, Røren, Niini, ?a?inková, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, 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., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppönen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, 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Tranchant, Christine, Zimmermann, Marie-Agathe, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johannes, Schlangen, Christiane, Werner, Cornelius J., Gelderblom, Harald, Priller, Josef, Prüß, Harald, Spruth, Eike Jakob, 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, Möller, Jens Carsten, Rissling, Ida, Mühlau, Mark, Peinemann, Alexander, Städtler, Michael, 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Marit, 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, van Walsem, Marleen R, Wehus, Ragnhild, Bjørgo, Kathrine, Fannemel, Madeleine, Gørvell, Per F., Lorentzen, Eirin, Koivisto, Susana Pro, Retterstøl, Lars, Stokke, Bodil, Bjørnevoll, Inga, Sando, Sigrid Botne, 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, Ferreira, Joaquim J., Coelho, Miguel, Guedes, Leonor Correia, Mendes, Tiago, Mestre, Tiago, Valadas, Anabela, Andrade, Carlos, Gago, Miguel, Garrett, Carolina, Guerra, Maria Rosália, Herrera, Carmen Durán, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badenes, Hernanz, Laura Casas, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Núria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, Jesús Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Blas, Fenollar, María, García, Rocío García-Ramos, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuñana, Mónica, Caldentey, Juan Garcia, Ventura, Marta Fatás, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Cubillo, Patricia Trigo, Alegre, Javier, Frech, Fernando Alonso, de Yébenes, Justo García, Ruíz, Pedro J García, Martínez-Descals, Asunción, Guerrero, Rosa, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivancos, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlos, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Arques, Penelope Navas, Rodríguez, María José Torres, Pastor, Barbara Vives, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolores, Ramos-Arroyo, Maria A., Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peña, José Chacón, Redondo, Luis, Carrillo, Fátima, Teresa Cáceres, María, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andres, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, 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, Simpson, Sheila A, 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, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Fullam, Ruth, Hunt, Sarah, Jones, Lesley ORCID: https://orcid.org/0000-0001-7156-8531, Jones, Una ORCID: https://orcid.org/0000-0001-7156-8531, Khalil, Hanan, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Price, Kathleen, Rosser, Anne ORCID: https://orcid.org/0000-0002-4716-4753, 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 ORCID: https://orcid.org/0000-0003-2316-510X, 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, Raman, Ashok, Chu, Carol, Hamer, Stephanie, Hobson, Emma, Jamieson, Stuart, Raman, Ashok, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, 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, Rosser, Elisabeth ORCID: https://orcid.org/0000-0002-4716-4753, Tabrizi, Sarah, Taylor, Rachel, Warner, Thomas, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Fullam, Ruth, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary ORCID: https://orcid.org/0000-0001-7156-8531, 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, Nemeth, Andrea H., 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, Lau, Puay Ngoh, Pica, Emmanul and Tan, Louis 2017. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. Lancet Neurology 16 (9) , pp. 701-711. 10.1016/S1474-4422(17)30161-8

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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 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Biosciences Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	Consortium co-authors: the TRACK-HD investigators, the REGISTRY investigators.
Publisher:	Elsevier
ISSN:	1474-4422
Funders:	The European Commission, CHDI Foundation, Medical Research Council UK, Brain Research Trust, Guarantors of Brain
Date of First Compliant Deposit:	25 July 2017
Date of Acceptance:	5 June 2017
Last Modified:	05 Nov 2024 18:30
URI:	https://orca.cardiff.ac.uk/id/eprint/102960

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