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19 results on '"Bagnoli, Silvia"'

1. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author: Swift, Imogen J., Rademakers, Rosa, Finch, Ni Cole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H.H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, Rohrer, Jonathan D., Swift, Imogen J., Rademakers, Rosa, Finch, Ni Cole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H.H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, and Rohrer, Jonathan D.
Abstract: Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usef
Published: 2024

2. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author: Reus, Lianne M., Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Ophoff, Roel A., Reus, Lianne M., Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, and Ophoff, Roel A.
Abstract: Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Published: 2021

3. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author: Reus, Lianne M., Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Ophoff, Roel A., Reus, Lianne M., Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, Pietro, Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, and Ophoff, Roel A.
Abstract: Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Published: 2021

4. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Author: Costa, Beatrice, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, Van Broeckhoven, Christine, Costa, Beatrice, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine
Abstract: ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the b
Published: 2020

5. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Author: Costa, Beatrice, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, Van Broeckhoven, Christine, Costa, Beatrice, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine
Abstract: ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the b
Published: 2020

6. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author: Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole A., Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel J., Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C., Chiang, Huei Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E., Cope, Tom E., Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H., Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy J.T., Huey, Edward D., Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G., Kristiansen, Mark, Lewis, Patrick A., Lleó, Alberto, Madhan, Gaganjit K., Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Mol, Merel O., Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Christopher M., Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande A.L., Puca, Annibale A., Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna M.T., Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Roßmeier, Carola, Rowe, James B., Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B., Santillo, Alexander F., Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, Eun Ran, Tagliavini, Fabrizio, Thompson, Jennifer C., Trojanowski, John Q., van Deerlin, Vivianna M., van der Zee, Julie, van Broeckhoven, Christine, van Rooij, Jeroen G.J., van Swieten, John C., Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L., Woodward, Cathy, Yokoyama, Jennifer S., Escott-Price, Valentina, Polke, James M., Ferrari, Raffaele, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole A., Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel J., Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C., Chiang, Huei Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E., Cope, Tom E., Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H., Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy J.T., Huey, Edward D., Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G., Kristiansen, Mark, Lewis, Patrick A., Lleó, Alberto, Madhan, Gaganjit K., Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Mol, Merel O., Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Christopher M., Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande A.L., Puca, Annibale A., Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna M.T., Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Roßmeier, Carola, Rowe, James B., Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B., Santillo, Alexander F., Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, Eun Ran, Tagliavini, Fabrizio, Thompson, Jennifer C., Trojanowski, John Q., van Deerlin, Vivianna M., van der Zee, Julie, van Broeckhoven, Christine, van Rooij, Jeroen G.J., van Swieten, John C., Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L., Woodward, Cathy, Yokoyama, Jennifer S., Escott-Price, Valentina, Polke, James M., and Ferrari, Raffaele
Abstract: Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectu, Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectu
Published: 2020

7. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author: Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole A., Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel J., Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C., Chiang, Huei Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E., Cope, Tom E., Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H., Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy J.T., Huey, Edward D., Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G., Kristiansen, Mark, Lewis, Patrick A., Lleó, Alberto, Madhan, Gaganjit K., Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Mol, Merel O., Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Christopher M., Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande A.L., Puca, Annibale A., Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna M.T., Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Roßmeier, Carola, Rowe, James B., Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B., Santillo, Alexander F., Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, Eun Ran, Tagliavini, Fabrizio, Thompson, Jennifer C., Trojanowski, John Q., van Deerlin, Vivianna M., van der Zee, Julie, van Broeckhoven, Christine, van Rooij, Jeroen G.J., van Swieten, John C., Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L., Woodward, Cathy, Yokoyama, Jennifer S., Escott-Price, Valentina, Polke, James M., Ferrari, Raffaele, Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A., Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole A., Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel J., Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C., Chiang, Huei Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E., Cope, Tom E., Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H., Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy J.T., Huey, Edward D., Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G., Kristiansen, Mark, Lewis, Patrick A., Lleó, Alberto, Madhan, Gaganjit K., Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Mol, Merel O., Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Christopher M., Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande A.L., Puca, Annibale A., Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna M.T., Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Roßmeier, Carola, Rowe, James B., Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B., Santillo, Alexander F., Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, Eun Ran, Tagliavini, Fabrizio, Thompson, Jennifer C., Trojanowski, John Q., van Deerlin, Vivianna M., van der Zee, Julie, van Broeckhoven, Christine, van Rooij, Jeroen G.J., van Swieten, John C., Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L., Woodward, Cathy, Yokoyama, Jennifer S., Escott-Price, Valentina, Polke, James M., and Ferrari, Raffaele
Abstract: Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectu, Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectu
Published: 2020

8. Alzheimer's Disease Progression : Factors Influencing Cognitive Decline

Author: Ferrari, Camilla, Lombardi, Gemma, Polito, Cristina, Lucidi, Giulia, Bagnoli, Silvia, Piaceri, Irene, Nacmias, Benedetta, Berti, Valentina, Rizzuto, Debora, Fratiglioni, Laura, Sorbi, Sandro, Ferrari, Camilla, Lombardi, Gemma, Polito, Cristina, Lucidi, Giulia, Bagnoli, Silvia, Piaceri, Irene, Nacmias, Benedetta, Berti, Valentina, Rizzuto, Debora, Fratiglioni, Laura, and Sorbi, Sandro
Abstract: Background: Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors. Objective: The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients. Methods: We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period. Results: Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) epsilon 4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated epsilon 4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non epsilon 4-carriers. Conclusion: At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.
Published: 2018
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9. No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients.

Author: UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baradaran-Heravi, Yalda, Dillen, Lubina, Nguyen, Hung Phuoc, Van Mossevelde, Sara, Baets, Jonathan, De Jonghe, Peter, Engelborghs, Sebastiaan, De Deyn, Peter P, Vandenbulcke, Mathieu, Vandenberghe, Rik, Van Damme, Philip, Cras, Patrick, Salmon, Eric, Synofzik, Matthis, Heutink, Peter, Wilke, Carlo, Simon-Sanchez, Javier, Rojas-Garcia, Ricard, Turon-Sans, Janina, Lleó, Alberto, Illán-Gala, Ignacio, Clarimón, Jordi, Borroni, Barbara, Padovani, Alessandro, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, Gelpi, Ellen, Sanchez-Valle, Raquel, Borrego-Ecija, Sergi, Matej, Radoslav, Parobkova, Eva, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, de Mendonça, Alexandre, Ferreira, Catarina, Fraidakis, Matthew J, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Almeida, Maria Rosário, Santana, Isabel, Van Broeckhoven, Christine, van der Zee, Julie, BELNEU Consortium, EU EOD Consortium, Ivanoiu, Adrian, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Baradaran-Heravi, Yalda, Dillen, Lubina, Nguyen, Hung Phuoc, Van Mossevelde, Sara, Baets, Jonathan, De Jonghe, Peter, Engelborghs, Sebastiaan, De Deyn, Peter P, Vandenbulcke, Mathieu, Vandenberghe, Rik, Van Damme, Philip, Cras, Patrick, Salmon, Eric, Synofzik, Matthis, Heutink, Peter, Wilke, Carlo, Simon-Sanchez, Javier, Rojas-Garcia, Ricard, Turon-Sans, Janina, Lleó, Alberto, Illán-Gala, Ignacio, Clarimón, Jordi, Borroni, Barbara, Padovani, Alessandro, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, Gelpi, Ellen, Sanchez-Valle, Raquel, Borrego-Ecija, Sergi, Matej, Radoslav, Parobkova, Eva, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, de Mendonça, Alexandre, Ferreira, Catarina, Fraidakis, Matthew J, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Almeida, Maria Rosário, Santana, Isabel, Van Broeckhoven, Christine, van der Zee, Julie, BELNEU Consortium, EU EOD Consortium, and Ivanoiu, Adrian
Abstract: We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated.
Published: 2018

10. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

Author: Pottier, Cyril, Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López de Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, Pickering-Brown, Stuart, Pottier, Cyril, Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López de Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, and Pickering-Brown, Stuart
Abstract: BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10-5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin.FindingsIndividuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases
Published: 2018

11. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations:a genome-wide association study

Author: Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López De Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, Nicole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, Van Blitterswijk, Marka, Dejesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, Eunran, Lopez, Oscar L, Wong, Tsz H, Van Rooij, Jeroen G J, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, Pickering-Brown, Stuart, Diehl-Schmid, Janine, Winkelmann, Juliane, Galimberti, Daniela, Graff, Caroline, Öijerstedt, Linn, Troakes, Claire, Al-Sarraj, Safa, Cruchaga, Carlos, Cairns, Nigel J, Rohrer, Jonathan D, Halliday, Glenda M, Kwok, John B, Van Swieten, John C, White, Charles L, Ghetti, Bernardino, Murell, Jill R, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Borroni, Barbara, Rossi, Giacomina, Tagliavini, Fabrizio, Wszolek, Zbigniew K, Petersen, Ronald C, Bigio, Eileen H, Grossman, Murray, Van Deerlin, Vivianna M, Seeley, William W, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, Biernacka, Joanna M, Rademakers, Rosa, Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López De Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, Nicole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, Van Blitterswijk, Marka, Dejesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, Eunran, Lopez, Oscar L, Wong, Tsz H, Van Rooij, Jeroen G J, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, Pickering-Brown, Stuart, Diehl-Schmid, Janine, Winkelmann, Juliane, Galimberti, Daniela, Graff, Caroline, Öijerstedt, Linn, Troakes, Claire, Al-Sarraj, Safa, Cruchaga, Carlos, Cairns, Nigel J, Rohrer, Jonathan D, Halliday, Glenda M, Kwok, John B, Van Swieten, John C, White, Charles L, Ghetti, Bernardino, Murell, Jill R, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Borroni, Barbara, Rossi, Giacomina, Tagliavini, Fabrizio, Wszolek, Zbigniew K, Petersen, Ronald C, Bigio, Eileen H, Grossman, Murray, Van Deerlin, Vivianna M, Seeley, William W, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, Biernacka, Joanna M, and Rademakers, Rosa
Published: 2018

12. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author: van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas García, Ricardo, Clarimon, Jordi, Lleó Bisa, Alberto, Diehl‐Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Håkan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger‐Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez‐Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega‐Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernández, Isabel, Boada Rovira, Mercè, Ruiz Laza, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sánchez Valle, Raquel, Lladó, Albert, Santana, Isabel, Rosário Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, Testi, Silvia, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas García, Ricardo, Clarimon, Jordi, Lleó Bisa, Alberto, Diehl‐Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Håkan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger‐Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez‐Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega‐Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernández, Isabel, Boada Rovira, Mercè, Ruiz Laza, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sánchez Valle, Raquel, Lladó, Albert, Santana, Isabel, Rosário Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, and Testi, Silvia
Abstract: We investigated the mutation spectrum of the TANK‐Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early‐Onset Dementia Consortium. We assessed pathogenicity of predicted protein‐truncating mutations by measuring loss of RNA expression. Functional effect of in‐frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB‐induced luciferase reporter assay and measuring phosphorylated TBK1. The protein‐truncating mutations led to the loss of transcript through nonsense‐mediated mRNA decay. For the in‐frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high‐risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD‐ALS.
Published: 2017

13. TBK1Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author: UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bâumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas-García, Ricardo, Clarimón, Jordi, Lleó, Alberto, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Hakan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez-Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega-Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernàndez, Isabel, Boada, Mercè, Ruiz, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sanchez-Valle, Raquel, Llado, Albert, Santana, Isabel, Rosàrio Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, Testi, Silvia, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bâumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas-García, Ricardo, Clarimón, Jordi, Lleó, Alberto, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Perneczky, Robert, Synofzik, Matthis, Just, Jennifer, Schöls, Ludger, Graff, Caroline, Thonberg, Hakan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre, Miltenberger-Miltényi, Gabriel, Simões do Couto, Frederico, Ramirez, Alfredo, Jessen, Frank, Heneka, Michael T., Gómez-Tortosa, Estrella, Danek, Adrian, Cras, Patrick, Vandenberghe, Rik, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc, Van Broeckhoven, Christine, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick, Dermaut, Bart, Versijpt, Jan, Michotte, Alex, Ivanoiu, Adrian, Deryck, Olivier, Bergmans, Bruno, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric, Pastor, Pau, Ortega-Cubero, Sara, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Hernàndez, Isabel, Boada, Mercè, Ruiz, Agustín, Sorbi, Sandro, Nacmias, Benedetta, Bagnoli, Silvia, Sanchez-Valle, Raquel, Llado, Albert, Santana, Isabel, Rosàrio Almeida, Maria, Frisoni, Giovanni B, Maetzler, Walter, Matej, Radoslav, Fraidakis, Matthew J., Kovacs, Gabor G., Fabrizi, Gian Maria, and Testi, Silvia
Abstract: We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
Published: 2017

14. Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

Author: Ferrari, R, Grassi, M, Graziano, F, Palluzzi, F, Archetti, S, Bonomi, E, Bruni, A, Maletta, R, Bernardi, L, Cupidi, C, Colao, R, Rainero, I, Rubino, E, Pinessi, L, Galimberti, D, Scarpini, E, Serpente, M, Nacmias, B, Piaceri, I, Bagnoli, S, Rossi, G, Giaccone, G, Tagliavini, F, Benussi, L, Binetti, G, Ghidoni, R, Singleton, A, Hardy, J, Momeni, P, Padovani, A, Borroni, B, Ferrari, Raffaele, Grassi, Mario, Graziano, Francesca, Palluzzi, Fernando, Archetti, Silvana, Bonomi, Elisa, Bruni, Amalia C., Maletta, Raffaele G., Bernardi, Livia, Cupidi, Chiara, Colao, Rosanna, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Galimberti, Daniela, Scarpini, Elio, Serpente, Maria, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Rossi, Giacomina, Giaccone, Giorgio, Tagliavini, Fabrizio, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Singleton, Andrew, Hardy, John, Momeni, Parastoo, Padovani, Alessandro, Borroni, Barbara, Ferrari, R, Grassi, M, Graziano, F, Palluzzi, F, Archetti, S, Bonomi, E, Bruni, A, Maletta, R, Bernardi, L, Cupidi, C, Colao, R, Rainero, I, Rubino, E, Pinessi, L, Galimberti, D, Scarpini, E, Serpente, M, Nacmias, B, Piaceri, I, Bagnoli, S, Rossi, G, Giaccone, G, Tagliavini, F, Benussi, L, Binetti, G, Ghidoni, R, Singleton, A, Hardy, J, Momeni, P, Padovani, A, Borroni, B, Ferrari, Raffaele, Grassi, Mario, Graziano, Francesca, Palluzzi, Fernando, Archetti, Silvana, Bonomi, Elisa, Bruni, Amalia C., Maletta, Raffaele G., Bernardi, Livia, Cupidi, Chiara, Colao, Rosanna, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Galimberti, Daniela, Scarpini, Elio, Serpente, Maria, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Rossi, Giacomina, Giaccone, Giorgio, Tagliavini, Fabrizio, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Singleton, Andrew, Hardy, John, Momeni, Parastoo, Padovani, Alessandro, and Borroni, Barbara
Abstract: In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95 CI: -4.64 to -3.07, p<2×10 -16 ) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5 of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
Published: 2017

15. Frontotemporal dementia and its subtypes: a genome-wide association study.

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernandez, Isabel, Ruiz, Agustin, Boada, Merce, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimon, Jordi, Lleo, Alberto, Blesa, Rafael, Waldo, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Veronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jorgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernandez, Isabel, Ruiz, Agustin, Boada, Merce, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimon, Jordi, Lleo, Alberto, Blesa, Rafael, Waldo, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Veronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jorgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, and Momeni, Parastoo
Abstract: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 x 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 x 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1.05 x 10(-8); odds ratio=1.204 [95% CI 1.11-1.30]), rs9268856 (p=5.51 x 10(-9); 0.809 [0.76-0.86]) and rs1980493 (p value=1.57 x 10(-8), 0.775 [0.69-0.86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2.44 x 10(-7); 0.814 [0.71-0.92]). Analysis of expression and methylation quantitative trait loci data suggested that the
Published: 2014

16. Frontotemporal dementia and its subtypes: a genome-wide association study.

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernandez, Isabel, Ruiz, Agustin, Boada, Merce, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimon, Jordi, Lleo, Alberto, Blesa, Rafael, Waldo, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Veronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jorgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B. J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernandez, Isabel, Ruiz, Agustin, Boada, Merce, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimon, Jordi, Lleo, Alberto, Blesa, Rafael, Waldo, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C. M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Veronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jorgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G. P., Seelaar, Harro, Pijnenburg, Yolande A. L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, and Momeni, Parastoo
Abstract: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 x 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 x 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1.05 x 10(-8); odds ratio=1.204 [95% CI 1.11-1.30]), rs9268856 (p=5.51 x 10(-9); 0.809 [0.76-0.86]) and rs1980493 (p value=1.57 x 10(-8), 0.775 [0.69-0.86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2.44 x 10(-7); 0.814 [0.71-0.92]). Analysis of expression and methylation quantitative trait loci data suggested that the
Published: 2014

17. Frontotemporal dementia and its subtypes: a genome-wide association study.

Author: Ferrari, Raffaele, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Ferrari, Raffaele, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N
Abstract: BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.FindingsWe identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that thes
Published: 2014

18. Frontotemporal dementia and its subtypes:a genome-wide association study

Author: Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John B J, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Mann, David M A, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes C M, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David, Josephs, Keith A, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise G P, Seelaar, Harro, Pijnenburg, Yolande A L, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John B J, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Mann, David M A, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes C M, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David, Josephs, Keith A, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise G P, Seelaar, Harro, Pijnenburg, Yolande A L, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, Hardy, John, and Momeni, Parastoo
Abstract: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci da
Published: 2014

19. Frontotemporal dementia and its subtypes:a genome-wide association study

Author: Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John B J, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Mann, David M A, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes C M, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David, Josephs, Keith A, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise G P, Seelaar, Harro, Pijnenburg, Yolande A L, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John B J, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Mann, David M A, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes C M, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Spillantini, Maria Grazia, Morris, Huw R, Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S, Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C, Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W, Graff-Radford, Neill R, Petersen, Ronald C, Knopman, David, Josephs, Keith A, Boeve, Bradley F, Parisi, Joseph E, Seeley, William W, Miller, Bruce L, Karydas, Anna M, Rosen, Howard, van Swieten, John C, Dopper, Elise G P, Seelaar, Harro, Pijnenburg, Yolande A L, Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A, Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B, Hardy, John, and Momeni, Parastoo
Abstract: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci da
Published: 2014

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19 results on '"Bagnoli, Silvia"'

1. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

2. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

3. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

4. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

5. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

6. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

7. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

8. Alzheimer's Disease Progression : Factors Influencing Cognitive Decline

9. No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients.

10. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

11. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations:a genome-wide association study

12. TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

13. TBK1Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

14. Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia

15. Frontotemporal dementia and its subtypes: a genome-wide association study.

16. Frontotemporal dementia and its subtypes: a genome-wide association study.

17. Frontotemporal dementia and its subtypes: a genome-wide association study.

18. Frontotemporal dementia and its subtypes:a genome-wide association study

19. Frontotemporal dementia and its subtypes:a genome-wide association study

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