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

Metzger, S; Walter, C; Riess, O; Roos, Ra; Nielsen, Je; Craufurd, D; Nguyen, Hp; REGISTRY Investigators of the European Huntington’s Disease Network:Bachoud Lévi AC,; Bentivoglio, Ar; Biunno, I; Bonelli, Rm; Burgunder, Jm; Dunnett, Sb; Ferreira, Jj; Handley, Oj; Heiberg, A; Illmann, T; Landwehrmeyer, G; Levey, J; Ramos Arroyo MA,; Nielsen, J; Koivisto, Sp; Päivärinta, M; Roos, Ra; Sebastián, Ar; Tabrizi, S; Vandenberghe, W; Verellen Dumoulin, C; Zaremba, J; Uhrová, T; Wahlström, J; Barth, K; Correia Guedes, L; Finisterra, Am; Garde, Mb; Bos, R; Betz, S; Callaghan, J; Fullam, R; Ecker, D; Nielsen, Mg; Handley, Oj; Hvalstedt, C; Held, C; Koppers, K; Laurà, M; Horta, Sm; Descals, Am; Díaz, Mf; Mestre, T; Minster, S; Monza, D; Mütze, L; Oehmen, M; Townhill, J; Orth, M; Padieu, H; Paterski, L; Peppa, N; Koivisto, Sp; Roedig, V; Rialland, A; Røren, N; Šašinková, P; Seliverstov, Y; Cubillo, Pt; van Walsem MR,; Wright, A; Silva, Wv; Witjes Anné MN,; Yudina, E; Zielonka, D; Zielonka, E; Zinzi, P; Bonelli, Rm; Herranhof, B; Holl, A; Kapfhammer, Hp; Koppitz, M; Magnet, M; Otti, D; Painold, A; Reisinger, K; Scheibl, M; Hecht, K; Lilek, S; Müller, N; Schöggl, H; Ullah, J; Ribaï, P; Verellen Dumoulin, C; Boogaerts, A; Vandenberghe, W; van Reijen, D; Klempíř, J; Majerová, V; Roth, J; Nielsen, J; Hjermind, L; Jacobsen, O; Vinthev Jensen, T; Larsen, Iu; Stockholm, J; Hiivola, H; Martikainen, K; Tuuha, K; Ignatius, J; Kärppä, M; Åman, J; Mustonen, A; Kajula, O; Santala, M; Allain, P; Guérid, Ma; Gohier, B; Olivier, A; Prundean, A; Scherer Gagou, C; Verny, C; Bost, M; Babiloni, B; Debruxelles, S; Duché, C; Goizet, C; Lafoucrière, D; Jameau, L; Spampinato, U; De Bruycker, C; Cabaret, M; Carette, As; Defebvre, L; Decorte, E; Delval, A; Delliaux, M; Destee, A; Dujardin, K; Peter, M; Plomhouse, L; Sablonnière, B; Simonin, C; Defebvre, L; Lemaire, Mh; Manouvrier, S; Thibault Tanchou, S; Vuillaume, I; Krystkowiak, P; Duru, C; Roussel, M; Wannepain, S; Berrissoul, H; Bellonet, M; Courtin, F; Mantaux, B; Fasquel, V; Godefroy, O; Azulay, Jp; Fluchère, F; Delfini, M; Eusebio, A; Mundler, L; Longato, N; Rudolf, G; Steinmetz, G; Tranchant, C; Wagner, C; Zimmermann, Ma; Marcel, C; Andrich, J; Ellrichmann, G; Hoffmann, R; Kaminski, B; Saft, C; Stamm, C; Boelmans, K; Ganos, C; Goerendt, I; Hidding, U; Lewerenz, J; Münchau, A; Orth, M; Schmalfeld, J; Stubbe, L; Zittel, S; Bürk, K; Möller, Jc; Rissling, I; Cormio, C; Sciruicchio, V; Serpino, C; de Tommaso, M; Capellari, Sabina; Cortelli, Pietro; Gallassi, R; Poda, Roberto; Rizzo, Giovanni; Scaglione, C; Abbruzzese, G; di Poggio MB,; Di Maria, E; Ferrandes, G; Mandich, P; Marchese, R; Albanese, A; Di Bella, D; Di Donato, S; Gellera, C; Genitrini, S; Mariotti, C; Monza, D; Nanetti, L; Paridi, D; Soliveri, P; Tomasello, C; Squitieri, F; Elifani, F; Maglione, V; Di Pardo, A; Alberti, S; Griguoli, A; Amico, E; Martino, T; Petrollini, M; Bentivoglio, Ar; Catalli, C; Di Giacopo, R; Fasano, A; Frontali, M; Guidubaldi, A; Ialongo, T; Jacopini, G; Loria, G; Piano, C; Chiara, P; Quaranta, D; Romano, S; Soleti, F; Spadaro, M; Zinzi, P; van Hout MS,; van Vugt JP,; de Weert, A; Bolwijn, Jj; Dekker, M; Leenders, Kl; Bos, R; Dumas, Em; van den Bogaard SJ,; Roos, Ra; 't Hart EP,; van Duijn, E; Kremer, B; Verstappen, Cc; Blinkenberg, Eø; Hauge, E; Tyvoll, H; Heiberg, A; van Walsem MR,; Frich, J; Aaserud, O; Wehus, R; Bjørgo, K; Fannemel, M; Gørvell, P; Lorentzen, E; Koivisto, Sp; Retterstøl, L; Overland, T; 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; Opala, G; Kłodowska Duda, G; Stompel, D; Banaszkiewicz, K; Boćwińska, D; Szczudlik, A; Rudzinska, M; Wójcik, M; Dec, M; Krawczyk, M; Bojakowska Jaremek, K; Szczygieł, E; Stenwak, A; Wasielewska, A; Bryl, A; Ciesielska, A; Klimberg, A; Marcinkowski, J; Sempołowicz, J; Zielonka, D; Samara, H; Wiśniewski, B; Janik, P; Gogol, A; Kwiecinski, H; Jamrozik, Z; Kaminska, A; Antczak, J; Jachinska, K; Rakowicz, M; Richter, P; Rola, R; Ryglewicz, D; Sienkiewicz Jarosz, H; Stępniak, I; Witkowski, G; Zdzienicka, E; Zaremba, J; Sułek, A; Krysa, W; Stepniak, I; Zieora Jakutowicz, K; Júlio, F; Januário, C; Mestre, T; Correia Guedes, L; Coelho, M; Mendes, T; Valadas, A; Ferreira, Jj; Andrade, C; Gago, M; Garrett, C; Guerra, Mr; Lima, J; Massano, J; Meireles, J; Herrera, Cd; Garcia, Pm; Barrero, F; Morales, B; Cubo, E; Mariscal, N; Sánchez, J; Alonso Frech, F; Perez, Mr; Fenollar, M; García, Rg; Pin Quiroga, P; Vázquez Rivera, S; Villanueva, C; Alegre, J; Bascuñana, M; Caldentey, Jg; Ventura, Mf; Ribas, Gg; de Yébenes JG,; Moreno, Jl; Cubillo, Pt; Ruíz, Pj; Martínez Descals, A; Artiga, Mj; Sánchez, V; Guerrero, R; Bárcenas, Ah; Díaz, Mf; Perea, Mf; Fortuna, L; Torres, Mm; Reinante, G; Moreau, Lv; Barbera, Ma; Guia, Db; Hernanz, Lc; Catena, Jl; Sebastián, Ar; Ferrer, Pq; Carruesco, Gt; Bas, J; Busquets, N; Calopa, M; Elorza, Md; López, Cd; Durán Sindreu Terol, S; Robert, Mf; Ruíz, Bg; Casado, Ag; Martínez, Ih; Viladrich, Cm; Cárdenas, Rp; Roca, E; Llesoy, Jr; Idiago, Jm; Vergara, Mr; García, Ss; Riballo, Av; González, Sg; Guisasola, Lm; Salvador, C; Martín, Es; González, M; Gorospe, A; Legarda, I; Arques, Pn; Rodríguez, Mj; Vives, B; Gaston, I; Ramos Arroyo MA,; Martinez Jaurrieta MD,; Moreno, Jm; Peña, Jc; Avarvarei, Ld; Bastida, Am; Recio, Mf; Vergé, Lr; Sánchez, Vs; Carrillo, F; Cáceres, Mt; Mir, P; Suarez, Mj; Loutfi, G; Olofsson, C; Stattin, El; Westman, L; Wikström, B; Pålhagen, Se; Paucar, M; Svenningsson, P; Reza Soltani TW,; Höglund, A; Sandström, B; Wahlström, J; Høsterey Ugander, U; Fredlund, G; Constantinescu, R; Neleborn Lingefjärd, L; Burgunder, Jm; Stebler, Y; Kaelin, A; Romero, I; Schüpbach, M; Zaugg, Sw; Miedzybrodzka, Z; Rae, D; Downie, L; Simpson, S; Summers, F; Ure, A; Jack, R; Matheson, K; Akhtar, S; Crooks, J; Curtis, A; de Souza, J; Rickards, H; Wright, J; Barker, Ra; O' Keefe, D; Di Pietro, A; Fisher, K; Goodman, A; Hill, S; Mason, S; Swain, R; Guzman, Nv; Bisson, J; Busse, M; Butcher, C; Callaghan, J; Clenaghan, C; Dunnett, S; Fullam, R; Handley, O; Hunt, S; Hughes, A; Johnstone, C; Jones, L; Jones, U; Khalil, H; Minster, S; Owen, M; Price, K; Rose, Le; Townhill, J; Rosser, A; Porteous, M; Edwards, M; C, Ho; Mcgill, M; Pearson, P; Brockie, P; Foster, J; Johns, N; Mckenzie, S; Rothery, J; Thomas, G; Yates, S; Burrows, L; Fletcher, A; Harding, A; Laver, F; Silva, M; Thomson, A; Rowett, L; Gallantrae, D; Longthorpe, M; Markova, I; Raman, A; Hamer, S; Yarduiman, P; Chu, C; Kraus, A; Wild, S; Musgrave, H; Rowett, L; Toscano, J; Jamieson, S; Hobson, E; Clayton, C; Dipple, H; Middleton, J; Freire Patino, D; Andrews, T; Dougherty, A; Kavalier, F; Golding, C; Laing, H; Lashwood, A; Robertson, D; Ruddy, D; Whaite, A; Santhouse, A; Patton, M; Peterson, M; Rose, S; Andrews, T; Bruno, S; Chu, E; 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; Craufurd, D; Fullam, R; Howard, L; Sollom, A; Snowden, J; Thompson, J; Callaghan, J; Jones, M; Murphy, H; Trender Gerhard, I; Rogers, D; Bek, J; Oughton, E; Johnson, L; Hare, M; Arran, N; Verstraelen, N; Partington Jones, L; Huson, S; Stopford, C; Westmoreland, L; Davidson, J; Morgan, K; Savage, L; Singh, B; Komati, S; Nemeth, Ah; Armstrong, R; Valentine, R; Siuda, G; 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; Nguyen, Hp

doi:10.1371/journal.pone.0068951

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.

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients / Metzger S;Walter C;Riess O;Roos RA;Nielsen JE;Craufurd D;Nguyen HP;REGISTRY Investigators of the European Huntington’s Disease Network:Bachoud-Lévi AC; Bentivoglio AR; Biunno I; Bonelli RM; Burgunder JM; Dunnett SB; Ferreira JJ; Handley OJ; Heiberg A; Illmann T; Landwehrmeyer G; Levey J; Ramos-Arroyo MA; Nielsen J; Koivisto SP; Päivärinta M; Roos RA; Sebastián AR; Tabrizi S; Vandenberghe W; Verellen-Dumoulin C; Zaremba J; Uhrová T; Wahlström J; Barth K; Correia-Guedes L; Finisterra AM; Garde MB; Bos R; Betz S; Callaghan J; Fullam R; Ecker D; Nielsen MG; Handley OJ; Hvalstedt C; Held C; Koppers K; Laurà M; Horta SM; Descals AM; Díaz MF; Mestre T; Minster S; Monza D; Mütze L; Oehmen M; Townhill J; Orth M; Padieu H; Paterski L; Peppa N; Koivisto SP; Roedig V; Rialland A; Røren N; Šašinková P; Seliverstov Y; Cubillo PT; van Walsem MR; Wright A; Silva WV; Witjes-Anné MN; Yudina E; Zielonka D; Zielonka E; Zinzi P; Bonelli RM; Herranhof B; Holl A; Kapfhammer HP; Koppitz M; Magnet M; Otti D; Painold A; Reisinger K; Scheibl M; Hecht K; Lilek S; Müller N; Schöggl H; Ullah J; Ribaï P; Verellen-Dumoulin C; Boogaerts A; Vandenberghe W; van Reijen D; Klempíř J; Majerová V; Roth J; Nielsen J; Hjermind L; Jacobsen O; Vinthev-Jensen T; Larsen IU; Stockholm J; Hiivola H; Martikainen K; Tuuha K; Ignatius J; Kärppä M; Åman J; Mustonen A; Kajula O; Santala M; Allain P; Guérid MA; Gohier B; Olivier A; Prundean A; Scherer-Gagou C; Verny C; Bost M; Babiloni B; Debruxelles S; Duché C; Goizet C; Lafoucrière D; Jameau L; Spampinato U; De Bruycker C; Cabaret M; Carette AS; Defebvre L; Decorte E; Delval A; Delliaux M; Destee A; Dujardin K; Peter M; Plomhouse L; Sablonnière B; Simonin C; Defebvre L; Lemaire MH; Manouvrier S; Thibault-Tanchou S; Vuillaume I; Krystkowiak P; Duru C; Roussel M; Wannepain S; Berrissoul H; Bellonet M; Courtin F; Mantaux B; Fasquel V; Godefroy O; Azulay JP; Fluchère F; Delfini M; Eusebio A; Mundler L; Longato N; Rudolf G; Steinmetz G; Tranchant C; Wagner C; Zimmermann MA; Marcel C; Andrich J; Ellrichmann G; Hoffmann R; Kaminski B; Saft C; Stamm C; Boelmans K; Ganos C; Goerendt I; Hidding U; Lewerenz J; Münchau A; Orth M; Schmalfeld J; Stubbe L; Zittel S; Bürk K; Möller JC; Rissling I; Cormio C; Sciruicchio V; Serpino C; de Tommaso M; Capellari S; Cortelli P; Gallassi R; Poda R; Rizzo G; Scaglione C; Abbruzzese G; di Poggio MB; Di Maria E; Ferrandes G; Mandich P; Marchese R; Albanese A; Di Bella D; Di Donato S; Gellera C; Genitrini S; Mariotti C; Monza D; Nanetti L; Paridi D; Soliveri P; Tomasello C; Squitieri F; Elifani F; Maglione V; Di Pardo A; Alberti S; Griguoli A; Amico E; Martino T; Petrollini M; Bentivoglio AR; Catalli C; Di Giacopo R; Fasano A; Frontali M; Guidubaldi A; Ialongo T; Jacopini G; Loria G; Piano C; Chiara P; Quaranta D; Romano S; Soleti F; Spadaro M; Zinzi P; van Hout MS; van Vugt JP; de Weert A; Bolwijn JJ; Dekker M; Leenders KL; Bos R; Dumas EM; van den Bogaard SJ; Roos RA; 't Hart EP; van Duijn E; Kremer B; Verstappen CC; Blinkenberg EØ; Hauge E; Tyvoll H; Heiberg A; van Walsem MR; Frich J; Aaserud O; Wehus R; Bjørgo K; Fannemel M; Gørvell P; Lorentzen E; Koivisto SP; Retterstøl L; Overland T; 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; Opala G; Kłodowska-Duda G; Stompel D; Banaszkiewicz K; Boćwińska D; Szczudlik A; Rudzinska M; Wójcik M; Dec M; Krawczyk M; Bojakowska-Jaremek K; Szczygieł E; Stenwak A; Wasielewska A; Bryl A; Ciesielska A; Klimberg A; Marcinkowski J; Sempołowicz J; Zielonka D; Samara H; Wiśniewski B; Janik P; Gogol A; Kwiecinski H; Jamrozik Z; Kaminska A; Antczak J; Jachinska K; Rakowicz M; Richter P; Rola R; Ryglewicz D; Sienkiewicz-Jarosz H; Stępniak I; Witkowski G; Zdzienicka E; Zaremba J; Sułek A; Krysa W; Stepniak I; Zieora-Jakutowicz K; Júlio F; Januário C; Mestre T; Correia-Guedes L; Coelho M; Mendes T; Valadas A; Ferreira JJ; Andrade C; Gago M; Garrett C; Guerra MR; Lima J; Massano J; Meireles J; Herrera CD; Garcia PM; Barrero F; Morales B; Cubo E; Mariscal N; Sánchez J; Alonso-Frech F; Perez MR; Fenollar M; García RG; Pin Quiroga P; Vázquez Rivera S; Villanueva C; Alegre J; Bascuñana M; Caldentey JG; Ventura MF; Ribas GG; de Yébenes JG; Moreno JL; Cubillo PT; Ruíz PJ; Martínez-Descals A; Artiga MJ; Sánchez V; Guerrero R; Bárcenas AH; Díaz MF; Perea MF; Fortuna L; Torres MM; Reinante G; Moreau LV; Barbera MA; Guia DB; Hernanz LC; Catena JL; Sebastián AR; Ferrer PQ; Carruesco GT; Bas J; Busquets N; Calopa M; Elorza MD; López CD; Durán-Sindreu Terol S; Robert MF; Ruíz BG; Casado AG; Martínez IH; Viladrich CM; Cárdenas RP; Roca E; Llesoy JR; Idiago JM; Vergara MR; García SS; Riballo AV; González SG; Guisasola LM; Salvador C; Martín ES; González M; Gorospe A; Legarda I; Arques PN; Rodríguez MJ; Vives B; Gaston I; Ramos-Arroyo MA; Martinez-Jaurrieta MD; Moreno JM; Peña JC; Avarvarei LD; Bastida AM; Recio MF; Vergé LR; Sánchez VS; Carrillo F; Cáceres MT; Mir P; Suarez MJ; Loutfi G; Olofsson C; Stattin EL; Westman L; Wikström B; Pålhagen SE; Paucar M; Svenningsson P; Reza-Soltani TW; Höglund A; Sandström B; Wahlström J; Høsterey-Ugander U; Fredlund G; Constantinescu R; Neleborn-Lingefjärd L; Burgunder JM; Stebler Y; Kaelin A; Romero I; Schüpbach M; Zaugg SW; Miedzybrodzka Z; Rae D; Downie L; Simpson S; Summers F; Ure A; Jack R; Matheson K; Akhtar S; Crooks J; Curtis A; de Souza J; Rickards H; Wright J; Barker RA; O' Keefe D; Di Pietro A; Fisher K; Goodman A; Hill S; Mason S; Swain R; Guzman NV; Bisson J; Busse M; Butcher C; Callaghan J; Clenaghan C; Dunnett S; Fullam R; Handley O; Hunt S; Hughes A; Johnstone C; Jones L; Jones U; Khalil H; Minster S; Owen M; Price K; Rose LE; Townhill J; Rosser A; Porteous M; Edwards M; Ho C; McGill M; Pearson P; Brockie P; Foster J; Johns N; McKenzie S; Rothery J; Thomas G; Yates S; Burrows L; Fletcher A; Harding A; Laver F; Silva M; Thomson A; Rowett L; Gallantrae D; Longthorpe M; Markova I; Raman A; Hamer S; Yarduiman P; Chu C; Kraus A; Wild S; Musgrave H; Rowett L; Toscano J; Jamieson S; Hobson E; Clayton C; Dipple H; Middleton J; Freire-Patino D; Andrews T; Dougherty A; Kavalier F; Golding C; Laing H; Lashwood A; Robertson D; Ruddy D; Whaite A; Santhouse A; Patton M; Peterson M; Rose S; Andrews T; Bruno S; Chu E; 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; Craufurd D; Fullam R; Howard L; Sollom A; Snowden J; Thompson J; Callaghan J; Jones M; Murphy H; Trender-Gerhard I; Rogers D; Bek J; Oughton E; Johnson L; Hare M; Arran N; Verstraelen N; Partington-Jones L; Huson S; Stopford C; Westmoreland L; Davidson J; Morgan K; Savage L; Singh B; Komati S; Nemeth AH; Armstrong R; Valentine R; Siuda G; 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; Nguyen HP. - In: PLOS ONE. - ISSN 1932-6203. - STAMPA. - 8:7(2013), pp. e68951.1-e68951.9. [10.1371/journal.pone.0068951]