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Lancet Neurol. 2017 Sep;16(9):701-711. doi: 10.1016/S1474-4422(17)30161-8. Epub 2017 Jun 20.

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

Collaborators (783)

Coleman A, Santos RD, Decolongon J, Sturrock A, Bardinet E, Ret CJ, Justo D, Lehericy S, Marelli C, Nigaud K, Valabrègue R, van den Bogaard S, Dumas EM, van der Grond J, t'Hart EP, Jurgens C, Witjes-Ane MN, 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, Fox NC, Gibbard C, Malone I, Crawford H, Whitehead D, Keenan S, Cash DM, Berna C, Bechtel N, Bohlen S, Man AH, 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, Andrews SC, Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli R, Burgunder JM, Dunnett S, Ferreira J, Handley O, Heiberg A, Illmann T, Landwehrmeyer GB, Levey J, Ramos-Arroyo MA, Nielsen J, Koivisto SP, Päivärinta M, Roos RAC, Sebastián AR, Tabrizi S, Vandenberghe W, Verellen-Dumoulin C, Uhrova T, Wahlström J, Zaremba J, Baake V, Barth K, Garde MB, Betz S, Bos R, Callaghan J, Come A, Guedes LC, Ecker D, Finisterra AM, Fullam R, Gilling M, Gustafsson L, Handley OJ, Hvalstedt C, Held C, Koppers K, Lamanna C, Laurà M, Descals AM, Martinez-Horta S, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Orth M, Padieu H, Paterski L, Peppa N, Koivisto SP, Di Renzo M, Rialland A, Røren N, Šašinková P, Timewell E, Townhill J, Cubillo PT, da Silva WV, van Walsem MR, Whalstedt C, Witjes-Ané MN, Witkowski G, Wright A, Zielonka D, Zielonka E, Zinzi P, Bonelli RM, Lilek S, Hecht K, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Müller N, Otti D, Painold A, Reisinger K, Scheibl M, Schöggl H, Ullah J, Braunwarth EM, Brugger F, Buratti L, Hametner EM, Hepperger C, Holas C, Hotter A, Hussl A, Müller C, Poewe W, Seppi K, Sprenger F, Wenning G, Boogaerts A, Calmeyn G, Delvaux I, Liessens D, Somers N, Dupuit M, Minet C, van Paemel D, Ribaï P, Verellen-Dumoulin C, Boogaerts A, Vandenberghe W, van Reijen D, Klempír J, Majerová V, Roth J, Stárková I, Hjermind LE, Jacobsen O, Nielsen JE, Larsen IU, Vinther-Jensen T, Hiivola H, Hyppönen H, Martikainen K, Tuuha K, Allain P, Bonneau D, Bost M, Gohier B, Guérid MA, Olivier A, Prundean A, Scherer-Gagou C, Verny C, Babiloni B, Debruxelles S, Duché C, Goizet C, Jameau L, Lafoucrière D, Spampinato U, Barthélémy R, De Bruycker C, Carette MCA, Defebvre EDL, Delliaux M, Delval A, Destee A, Dujardin K, Lemaire MH, Manouvrier S, Peter M, Plomhouse L, Sablonnière B, Simonin C, Thibault-Tanchou S, Vuillaume I, Bellonet M, Berrissoul H, Blin S, Courtin F, Duru C, Fasquel V, Godefroy O, Krystkowiak P, Mantaux B, Roussel M, Wannepain S, Azulay JP, Delfini M, Eusebio A, Fluchere F, Mundler L, Anheim M, Julié C, Boukbiza OL, Longato N, Rudolf G, Tranchant C, Zimmermann MA, Kosinski CM, Milkereit E, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Gelderblom H, Priller J, Prüß H, Spruth EJ, Ellrichmann G, Herrmann L, Hoffmann R, Kaminski B, Kotz P, Prehn C, Saft C, Lange H, Maiwald R, Löhle M, Maass A, Schmidt S, Bosredon C, Storch A, Wolz A, Wolz M, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Heinicke W, Hidding U, Lewerenz J, Münchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Diercks G, Dressler D, Gorzolla H, Schrader C, Tacik P, Ribbat M, Longinus B, Bürk K, Möller JC, Rissling I, Mühlau M, Peinemann A, Städtler M, Weindl A, Winkelmann J, Ziegler C, Bechtel N, Beckmann H, Bohlen S, Hölzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Schepers S, Weber N, Dose M, Leythäuser G, Marquard R, Raab T, Wiedemann A, Barth K, Buck A, Connemann J, Ecker D, Geitner C, Held C, Kesse A, Landwehrmeyer B, Lang C, Lewerenz J, Lezius F, Nepper S, Niess A, Orth M, Schneider A, Schwenk D, Süßmuth S, Trautmann S, Weydt P, Cormio C, Sciruicchio V, Serpino C, de Tommaso M, Capellari S, Cortelli P, Galassi R, Rizzo G, Poda R, Scaglione C, Bertini E, Ghelli E, Ginestroni A, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, di Poggio MB, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Castaldo A, Di Donato S, Gellera C, Genitrini S, Mariotti C, Monza D, Nanetti L, Paridi D, Soliveri P, Tomasello C, De Michele G, Di Maio L, Massarelli M, Peluso S, Roca A, Russo CV, Salvatore E, Sorrentino P, Amico E, Favellato M, Griguoli A, Mazzante I, Petrollini M, Squitieri F, D'Alessio B, Esposito C, Bentivoglio R, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Piano C, Romano S, Soleti F, Spadaro M, Zinzi P, van Hout MSE, Verhoeven ME, van Vugt JPP, de Weert AM, Bolwijn JJW, Dekker M, Kremer B, Leenders KL, van Oostrom JCH, van den Bogaard SJA, Bos R, Dumas EM, 't Hart EP, Roos RAC, Kremer B, Verstappen CCP, Aaserud O, C JF, Heiberg A, van Walsem MR, Wehus R, Bjørgo K, Fannemel M, Gørvell PF, Lorentzen E, Koivisto SP, Retterstøl L, Stokke B, Bjørnevoll I, Sando SB, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszcyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Klodowska-Duda G, Opala G, Stompel D, Banaszkiewicz K, Bocwinska D, Bojakowska-Jaremek K, Dec M, Krawczyk M, Rudzinska M, Szczygiel E, Szczudlik A, Wasielewska A, Wójcik M, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Samara H, Sempolowicz J, Zielonka D, Gogol A, Janik P, Kwiecinski H, Jamrozik Z, Antczak J, Jachinska K, Krysa W, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Stepniak I, Sulek A, Witkowski G, Zaremba J, Zdzienicka E, Zieora-Jakutowicz K, Ferreira JJ, Coelho M, Guedes LC, Mendes T, Mestre T, Valadas A, Andrade C, Gago M, Garrett C, Guerra MR, Herrera CD, Garcia PM, Barbera MA, Guia DB, Hernanz LC, Catena JL, Ferrer PQ, Sebastián AR, Carruesco GT, Bas J, Busquets N, Calopa M, Robert MF, Viladrich CM, Idiago JMR, Riballo AV, Cubo E, Polo CG, Mariscal N, Rivadeneyra PJ, Barrero F, Morales B, Fenollar M, García RG, Ortega P, Villanueva C, Alegre J, Bascuñana M, Caldentey JG, Ventura MF, Ribas GG, de Yébenes JG, Moreno JLL, Cubillo PT, Alegre J, Frech FA, de Yébenes JG, Ruíz PJG, Martínez-Descals A, Guerrero R, Artiga MJS, Sánchez V, Perea MFN, Fortuna L, Manzanares S, Reinante G, Torres MMA, Moreau LV, González González S, Guisasola LM, Salvador C, Martín ESS, Ramirez IL, Gorospe A, Lopera MR, Arques PN, Rodríguez MJT, Pastor BV, Gaston I, Martinez-Jaurrieta MD, Ramos-Arroyo MA, Moreno JMG, Lucena CM, Damas F, Cortegana HEP, Peña JC, Redondo L, Carrillo F, Teresa Cáceres M, Mir P, Suarez MJL, Vargas-González L, Bosca ME, Brugada FC, Burguera JA, Campos A, Vilaplana GCP, Berglund P, Constantinescu R, Fredlund G, Høsterey-Ugander U, Linnsand P, Neleborn-Lingefjärd L, Wahlström J, Wentzel M, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B, Burgunder JM, Stebler Y, Kaelin A, Romero I, Schüpbach M, Weber Zaugg S, Hauer M, Gonzenbach R, Jung HH, Mihaylova V, Petersen J, Jack R, Matheson K, Miedzybrodzka Z, Rae D, Simpson SA, Summers F, Ure A, Vaughan V, Akhtar S, Crooks J, Curtis A, de Souza J, Piedad J, Rickards H, Wright J, Coulthard E, Gethin L, Hayward B, Sieradzan K, Wright A, Armstrong M, Barker RA, O'Keefe D, Di Pietro A, Fisher K, Goodman A, Hill S, Kershaw A, Mason S, Paterson N, Raymond L, Swain R, Guzman NV, Busse M, Butcher C, Callaghan J, Dunnett S, Clenaghan C, Fullam R, Handley O, Hunt S, Jones L, Jones U, Khalil H, Minster S, Owen M, Price K, Rosser A, Townhill J, Edwards M, Ho C, Hughes T, McGill M, Pearson P, Porteous M, Smith P, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Burrows L, Chu C, Fletcher A, Gallantrae D, Hamer S, Harding A, Klöppel S, Kraus A, Laver F, Lewis M, Longthorpe M, Markova I, Raman A, Robertson N, Silva M, Thomson A, Wild S, Yardumian P, Chu C, Evans C, Gallentrae D, Hamer S, Kraus A, Markova I, Raman A, Chu C, Hamer S, Hobson E, Jamieson S, Kraus A, Markova I, Raman A, Musgrave H, Rowett L, Toscano J, Wild S, Yardumian P, Bourne C, Clapton J, Clayton C, Dipple H, Freire-Patino D, Grant J, Gross D, Hallam C, Middleton J, Murch A, Thompson C, Alusi S, Davies R, Foy K, Gerrans E, Pate L, Andrews T, Dougherty A, Golding C, Kavalier F, Laing H, Lashwood A, Robertson D, Ruddy D, Santhouse A, Whaite A, Andrews T, Bruno S, Doherty K, Golding C, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Robertson N, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Arran N, Bek J, Callaghan J, Craufurd D, Fullam R, Hare M, Howard L, Huson S, Johnson L, Jones M, Murphy H, Oughton E, Partington-Jones L, Rogers D, Sollom A, Snowden J, Stopford C, Thompson J, Trender-Gerhard I, Verstraelen N, Westmoreland L, Armstrong R, Dixon K, Nemeth AH, Siuda G, Valentine R, Harrison D, Hughes M, Parkinson A, Soltysiak B, Bandmann O, Bradbury A, Gill P, Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O'Donovan K, Peppa N, Taylor C, Tidswell K, Quarrell O, Burgunder JM, Lau PN, Pica E, Tan L.

Erratum in

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.

PMID:
28642124
DOI:
10.1016/S1474-4422(17)30161-8
[Indexed for MEDLINE]

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