The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

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

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

β-Defensin genomic copy number does not influence the age of onset in Huntington's Disease

none498siHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammations is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2)- encoded by DEFB4- is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD.openVittori A, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ, Bachoud-Levi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer GB, Levey J, Martinez-Jaurrieta MD, Nielsen JE, Pro Koivisto S, Piiiviirinta M, Roos RA, Sebastian AR, Tabrizi SJ, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrova T, Wahlstrom J, Barth K, Correia-Guedes L, Finisterra AM, Bascuiiana Garde M, Betz S, Bos R, Ecker D, Handley OJ, Held C, Koppers K, Laura M, Descals AM, Mestre T, Monza D, Townhill J, Padieu H, Paterski L, Peppa N, Rialland A, Røren N, Sasinkova P, Trigo Cubillo P, van Walsem M, Witjes-Ane MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Bonelli RM, Herranhof B, HOd A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinge K, Scheib M, Hecht K, Lilek S, Muller N, Schoggl H, Ullah J, Ribal P, Verellen-Dumoulin C, Klempff J, Majerova V, Roth J, Hjermind LE, Jakobsen O, Vinthev-Jensen T, Larsen IU, Nielsen JE, Stokholm J, Hiivola H, Martikainen K, Tuuha K, Santala M, Milkereit E, Kosinski CM, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Lange H, Lohle M, Schmidt S, Storch A, Wolz A, Wolz M, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Hidding U, Lewerenz J, Miinchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Heinicke W, Ribbat M, Longinus B, Miihlau M, Peinemann A, Stiidtler M, Weindl A, Winkelmann J, Ziegler C, Bechtel N, Beckmann H, Bohlen S, Holzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Schepers S, Dose M, Leythaeuser G, Marquard R, Raab T, Schrenk C, Schuierer M, Barth K, Buck A, Ecker D, Eschenbach C, Held C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Orth M, Schwenk D, Siissmuth S, Trautmann S, Weydt P, Cormio C, de Tommaso M, Sciruicchio V, Serpino C, Ghelli E, Ginestroni A, Bertini E, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, Ferrandes MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Monza D, Soliveri P, Tomasello C, De Michele G, DiMaio L, Massarelli M, Rinaldi C, Roca A, Rossi F, Russo CV, Salvatore E, Sorrentino P, Tucci T, De Nicola A, Elifani F, Petrollini M, Martino T, Lovo F, Squitieri F, Bentivoglio AR, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Piccininni C, Quaranta D, Romano S, Soleti F, Spadaro M, Zinzi P, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Neurologie P, Dekker M, Neurologie P, Leenders KL, van Oostrom JC, Bos R, Dumas EM, Jurgens CK, van den Bogaard SJ, Roos RA, 't Hart EP, Kremer B, Verstappen CC, Heiberg A, van Walsem MR, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, 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, Blaszczyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Klodowska G, Stompel D, Ciach-Wysocka E, Banaszkiewicz K, Boewiriska D, Bojakowska-Jaremek K, Neurologii A, Dec M, Krawczyk M, Rudziriska M, Szczudlik A, Szczygiel E, Wasielewska A, Wojcik M, Wojcik M, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Samara H, Sempolowicz J, Zielonka D, Janik P, Kalbarczyk A, Kwiecinski H, Jamrozik Z, Antczak J, Jachinska K, Krysa W, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Sulek A, Witkowski G, Zdzienicka E, Zaremba J, Zieora-Jakutowicz K, Coelho M, Correia-Guedes L, Ferreira JJ, Mestre T, Mendes T, Valadas A, Andrade C, Joao PS, Gago M, Garrett C, Joao PS, Guerra MR, Joao PS, Solis P, Herrera CD, Garcia PM, Cubo E, Mariscal N, Sanchez J, Barrero FJ, Alonso-Frech F, Perez MR, Fenollar M, Garda R, Rivera SV, Villanueva C, Alegre J, Bascuiiana M, Ventura MF, Ribas GG, Moreno JL, Cubillo PT, Rufz PJ, Frech FA, Dfaz J, Guerrero R, Dfaz J, Artiga MJ, Dfaz J, Sanchez V, Alcaraz LF, de Ia Arrixaca V, Manzanares S, de Ia Arrixaca V, Perea MF, Reinante G, Arrixaca Ia, Torres MM, Moreau LV, de Ia Arrixaca V, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastian R, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Buongiorno MT, Munoz E, Elorza MD, Lopez CD, Terol DS, Robert MF, Rufz BG, Casado AG, Martinez IH, Viladrich CM, Pons R, Roca E, Llesoy JR, Idiago JM, Vergara MR, Garcia SS, Riballo AV, Hoglund A, Palhagen SE, Paucar M, Sandstrom B, Svenningsson P, Reza-Soltani TW, Burgunder JM, Kaelin A, Romero I, Schupbach M, Stebler Y, Zaugg SW, Akhtar S, Crooks J, Curtis A, de Souza J, Rickards H, Wright J, Barker RA, Di Pietro A, Fisher K, Goodman AO, Hill S, Kershaw A, Mason S, O'Keefe D, Swain R, Guzman NV, Busse M, Butcher C, Clenaghan C, Dunnett S, Fullam R, Jones L, Jones U, Khalil H, Minster S, Owen M, Hunt S, Price K, Rosser A, Townhill J, Edwards M, Ho C, McGill M, Pearson P, Porteous M, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Burrows L, Chu C, Fletcher A, Gallantrae D, Harding A, Hamer S, Kraus A, Laver F, Longthorpe M, Markova I, Raman A, Silva M, Thomson A, Wild S, Yardumian P, Hobson E, Jamieson S, Musgrave H, Rowett L, Toscano J, Wild S, Yardumian P, Clayton C, Dipple H, Middleton J, Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Andrews T, Bruno S, Doherty K, Lahiri N, Novak M, Patel A, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Arran N, Bek J, Callaghan J, Craufurd D, Fullam R, Howard L, Hare M, Huson S, Johnson L, Jones M, Murphy H, Oughton E, Partington-Janes L, Rogers D, Snowden J, Sollom A, Stopford C, Thompson J, Trender-Gerhard I.Vittori, A; Orth, M; Roos, Ra; Outeiro, Tf; Giorgini, F; Hollox, Ej; Bachoud-Levi, Ac; Bentivoglio, Ar; Biunno, I; Bonelli, Rm; Burgunder, Jm; Dunnett, Sb; Ferreira, Jj; Handley, Oj; Heiberg, A; Illmann, T; Landwehrmeyer, Gb; Levey, J; Martinez-Jaurrieta, Md; Nielsen, Je; Pro Koivisto, S; Piiiviirinta, M; Roos, Ra; Sebastian, Ar; Tabrizi, Sj; Vandenberghe, W; Verellen-Dumoulin, C; Zaremba, J; Uhrova, T; Wahlstrom, J; Barth, K; Correia-Guedes, L; Finisterra, Am; Bascuiiana Garde, M; Betz, S; Bos, R; Ecker, D; Handley, Oj; Held, C; Koppers, K; Laura, M; Descals, Am; Mestre, T; Monza, D; Townhill, J; Padieu, H; Paterski, L; Peppa, N; Rialland, A; Røren, N; Sasinkova, P; Trigo Cubillo, P; van Walsem, M; Witjes-Ane, Mn; Yudina, E; Zielonka, D; Zielonka, E; Zinzi, P; Bonelli, Rm; Herranhof, B; Hod, A; Kapfhammer, Hp; Koppitz, M; Magnet, M; Otti, D; Painold, A; Reisinge, K; Scheib, M; Hecht, K; Lilek, S; Muller, N; Schoggl, H; Ullah, J; Ribal, P; Verellen-Dumoulin, C; Klempff, J; Majerova, V; Roth, J; Hjermind, Le; Jakobsen, O; Vinthev-Jensen, T; Larsen, Iu; Nielsen, Je; Stokholm, J; Hiivola, H; Martikainen, K; Tuuha, K; Santala, M; Milkereit, E; Kosinski, Cm; Probst, D; Reetz, K; Sass, C; Schiefer, J; Schlangen, C; Werner, Cj; Andrich, J; Ellrichmann, G; Hoffmann, R; Kaminski, B; Saft, C; Stamm, C; Lange, H; Lohle, M; Schmidt, S; Storch, A; Wolz, A; Wolz, M; Capetian, P; Lambeck, J; Zucker, B; Boelmans, K; Ganos, C; Hidding, U; Lewerenz, J; Miinchau, A; Orth, M; Schmalfeld, J; Stubbe, L; Zittel, S; Heinicke, W; Ribbat, M; Longinus, B; Miihlau, M; Peinemann, A; Stiidtler, M; Weindl, A; Winkelmann, J; Ziegler, C; Bechtel, N; Beckmann, H; Bohlen, S; Holzner, E; Lange, H; Reilmann, R; Rohm, S; Rumpf, S; Schepers, S; Dose, M; Leythaeuser, G; Marquard, R; Raab, T; Schrenk, C; Schuierer, M; Barth, K; Buck, A; Ecker, D; Eschenbach, C; Held, C; Landwehrmeyer, B; Lezius, F; Nepper, S; Niess, A; Orth, M; Schwenk, D; Siissmuth, S; Trautmann, S; Weydt, P; Cormio, C; de Tommaso, M; Sciruicchio, V; Serpino, C; Ghelli, E; Ginestroni, A; Bertini, E; Massaro, F; Mechi, C; Paganini, M; Piacentini, S; Pradella, S; Romoli, Am; Sorbi, S; Abbruzzese, G; Ferrandes, Mb; Di Maria, E; Ferrandes, G; Mandich, P; Marchese, R; Di Donato, S; Gellera, C; Genitrini, S; Mariotti, C; Nanetti, L; Monza, D; Soliveri, P; Tomasello, C; De Michele, G; Dimaio, L; Massarelli, M; Rinaldi, C; Roca, A; Rossi, F; Russo, Cv; Salvatore, E; Sorrentino, P; Tucci, T; De Nicola, A; Elifani, F; Petrollini, M; Martino, T; Lovo, F; Squitieri, F; Bentivoglio, Ar; Catalli, C; Di Giacopo, R; Fasano, A; Frontali, M; Guidubaldi, A; Ialongo, T; Jacopini, G; Loria, G; Piano, C; Piccininni, C; Quaranta, D; Romano, S; Soleti, F; Spadaro, M; Zinzi, P; van Hout, Ms; van Vugt, Jp; de Weert, A; Bolwijn, Jj; Neurologie, P; Dekker, M; Neurologie, P; Leenders, Kl; van Oostrom, Jc; Bos, R; Dumas, Em; Jurgens, Ck; van den Bogaard, Sj; Roos, Ra; 't Hart, Ep; Kremer, B; Verstappen, Cc; Heiberg, A; van Walsem, Mr; Frich, J; Aaserud, O; Wehus, R; Bjørgo, K; Fannemel, M; Gørvell, P; 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; Blaszczyk, M; Boczarska-Jedynak, M; Ciach-Wysocka, E; Gorzkowska, A; Jasinska-Myga, B; Opala, G; Klodowska, G; Stompel, D; Ciach-Wysocka, E; Banaszkiewicz, K; Boewiriska, D; Bojakowska-Jaremek, K; Neurologii, A; Dec, M; Krawczyk, M; Rudziriska, M; Szczudlik, A; Szczygiel, E; Wasielewska, A; Wojcik, M; Wojcik, M; Bryl, A; Ciesielska, A; Klimberg, A; Marcinkowski, J; Samara, H; Sempolowicz, J; Zielonka, D; Janik, P; Kalbarczyk, A; Kwiecinski, H; Jamrozik, Z; Antczak, J; Jachinska, K; Krysa, W; Rakowicz, M; Richter, P; Rola, R; Ryglewicz, D; Sienkiewicz-Jarosz, H; Sulek, A; Witkowski, G; Zdzienicka, E; Zaremba, J; Zieora-Jakutowicz, K; Coelho, M; Correia-Guedes, L; Ferreira, Jj; Mestre, T; Mendes, T; Valadas, A; Andrade, C; Joao, Ps; Gago, M; Garrett, C; Joao, Ps; Guerra, Mr; Joao, Ps; Solis, P; Herrera, Cd; Garcia, Pm; Cubo, E; Mariscal, N; Sanchez, J; Barrero, Fj; Alonso-Frech, F; Perez, Mr; Fenollar, M; Garda, R; Rivera, Sv; Villanueva, C; Alegre, J; Bascuiiana, M; Ventura, Mf; Ribas, Gg; Moreno, Jl; Cubillo, Pt; Rufz, Pj; Frech, Fa; Dfaz, J; Guerrero, R; Dfaz, J; Artiga, Mj; Dfaz, J; Sanchez, V; Alcaraz, Lf; de Ia Arrixaca, V; Manzanares, S; de Ia Arrixaca, V; Perea, Mf; Reinante, G; Arrixaca, Ia; Torres, Mm; Moreau, Lv; de Ia Arrixaca, V; Barbera, Ma; Guia, Db; Hernanz, Lc; Catena, Jl; Sebastian, R; Ferrer, Pq; Carruesco, Gt; Bas, J; Busquets, N; Calopa, M; Buongiorno, Mt; Munoz, E; Elorza, Md; Lopez, Cd; Terol, Ds; Robert, Mf; Rufz, Bg; Casado, Ag; Martinez, Ih; Viladrich, Cm; Pons, R; Roca, E; Llesoy, Jr; Idiago, Jm; Vergara, Mr; Garcia, Ss; Riballo, Av; Hoglund, A; Palhagen, Se; Paucar, M; Sandstrom, B; Svenningsson, P; Reza-Soltani, Tw; Burgunder, Jm; Kaelin, A; Romero, I; Schupbach, M; Stebler, Y; Zaugg, Sw; Akhtar, S; Crooks, J; Curtis, A; de Souza, J; Rickards, H; Wright, J; Barker, Ra; Di Pietro, A; Fisher, K; Goodman, Ao; Hill, S; Kershaw, A; Mason, S; O'Keefe, D; Swain, R; Guzman, Nv; Busse, M; Butcher, C; Clenaghan, C; Dunnett, S; Fullam, R; Jones, L; Jones, U; Khalil, H; Minster, S; Owen, M; Hunt, S; Price, K; Rosser, A; Townhill, J; Edwards, M; Ho, C; Mcgill, M; Pearson, P; Porteous, M; Brockie, P; Foster, J; Johns, N; Mckenzie, S; Rothery, J; Thomas, G; Yates, S; Burrows, L; Chu, C; Fletcher, A; Gallantrae, D; Harding, A; Hamer, S; Kraus, A; Laver, F; Longthorpe, M; Markova, I; Raman, A; Silva, M; Thomson, A; Wild, S; Yardumian, P; Hobson, E; Jamieson, S; Musgrave, H; Rowett, L; Toscano, J; Wild, S; Yardumian, P; Clayton, C; Dipple, H; Middleton, J; Patino, D; Andrews, T; Dougherty, A; Kavalier, F; Golding, C; Laing, H; Lashwood, A; Robertson, D; Ruddy, D; Whaite, A; Santhouse, A; Andrews, T; Bruno, S; Doherty, K; Lahiri, N; Novak, M; Patel, A; Rosser, E; Tabrizi, S; Taylor, R; Warner, T; Wild, E; Arran, N; Bek, J; Callaghan, J; Craufurd, D; Fullam, R; Howard, L; Hare, M; Huson, S; Johnson, L; Jones, M; Murphy, H; Oughton, E; Partington-Janes, L; Rogers, D; Snowden, J; Sollom, A; Stopford, C; Thompson, J; Trender-Gerhard, I

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

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

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

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

Suicidal ideation in a European Huntington's disease population

BACKGROUND: Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS: The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS: As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines

Suicidal ideation in a European Huntington's disease population

Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD. METHODS: The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis. RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive. LIMITATIONS: As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated. CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines