Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M., McLaughlin, Russell L., Diekstra, Frank P., Pulit, Sara L., van der Spek, Rick A. A., Vosa, Urmo, de Jong, Simone, Robinson, Matthew R., Yang, Jian, Fogh, Isabella, van Doormaal, Perry T. C., Tazelaar, Gijs H. P., Koppers, Max, Blokhuis, Anna M., Sproviero, William, Jones, Ashley R., Kenna, Kevin P., van Eijk, Kristel R., Harschnitz, Oliver, Schellevis, Raymond D., Brands, William J., Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavac, Metka, Koritnik, Blazi, Zidar, Janez, Leonardis, Lea, Groselj, Leja Dolenc, Millecamps, Stephanie, Salachas, Francois, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S., Rojas-Garcia, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A., Staats, Kim A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M., Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Basak, A. Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R., Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine A. M., Saker-Delye, Safaa, Duerr, Alexandra, Wood, Nicholas W., Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Noethen, Markus M., Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-Francois, Uitterlinden, Andre G., Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, Blauw, Hylke M., van der Kooi, Anneke J., de Visser, Marianne, Goris, An, Weber, Markus, Shaw, Christopher E., Smith, Bradley N., Pansarasa, Orietta, Cereda, Cristina, Del Bo, Roberto, Comi, Giacomo P., D'Alfonso, Sandra, Bertolin, Cinzia, Soraru, Gianni, Mazzini, Letizia, Pensato, Viviana, Gellera, Cinzia, Tiloca, Cinzia, Ratti, Antonia, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Arcuti, Simona, Capozzo, Rosa, Zecca, Chiara, Lunetta, Christian, Penco, Silvana, Riva, Nilo, Padovani, Alessandro, Filosto, Massimiliano, Muller, Bernard, Stuit, Robbert Jan, Blair, Ian, Zhang, Katharine, McCann, Emily P., Fifita, Jennifer A., Nicholson, Garth A., Rowe, Dominic B., Pamphlett, Roger, Kiernan, Matthew C., Grosskreutz, Julian, Witte, Otto W., Ringer, Thomas, Prell, Tino, Stubendorff, Beatrice, Kurth, Ingo, Huebner, Christian A., Leigh, P. Nigel, Casale, Federico, Chio, Adrian, Beghi, Ettore, Pupillo, Elisabetta, Tortelli, Rosanna, Logroscino, Giancarlo, Powell, John, Ludolph, Albert C., Weishaupt, Jochen H., Robberecht, Wim, Van Damme, Philip, Franke, Lude, Pers, Tune H., Brown, Robert H., Glass, Jonathan D., Landers, John E., Hardiman, Orla, Andersen, Peter M., Corcia, Philippe, Vourc'h, Patrick, Silani, Vincenzo, Wray, Naomi R., Visscher, Peter M., de Bakker, Paul I. W., van Es, Michael A., Pasterkamp, R. Jeroen, Lewis, Cathryn M., Breen, Gerome, Al-Chalabi, Ammar, van den Berg, Leonard H. and Veldink, Jan H. (2016) Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics, 48 9: 1043-1048. doi:10.1038/ng.3622


Author van Rheenen, Wouter
Shatunov, Aleksey
Dekker, Annelot M.
McLaughlin, Russell L.
Diekstra, Frank P.
Pulit, Sara L.
van der Spek, Rick A. A.
Vosa, Urmo
de Jong, Simone
Robinson, Matthew R.
Yang, Jian
Fogh, Isabella
van Doormaal, Perry T. C.
Tazelaar, Gijs H. P.
Koppers, Max
Blokhuis, Anna M.
Sproviero, William
Jones, Ashley R.
Kenna, Kevin P.
van Eijk, Kristel R.
Harschnitz, Oliver
Schellevis, Raymond D.
Brands, William J.
Medic, Jelena
Menelaou, Androniki
Vajda, Alice
Ticozzi, Nicola
Lin, Kuang
Rogelj, Boris
Vrabec, Katarina
Ravnik-Glavac, Metka
Koritnik, Blazi
Zidar, Janez
Leonardis, Lea
Groselj, Leja Dolenc
Millecamps, Stephanie
Salachas, Francois
Meininger, Vincent
de Carvalho, Mamede
Pinto, Susana
Mora, Jesus S.
Rojas-Garcia, Ricardo
Polak, Meraida
Chandran, Siddharthan
Colville, Shuna
Swingler, Robert
Morrison, Karen E.
Shaw, Pamela J.
Hardy, John
Orrell, Richard W.
Pittman, Alan
Sidle, Katie
Fratta, Pietro
Malaspina, Andrea
Topp, Simon
Petri, Susanne
Abdulla, Susanne
Drepper, Carsten
Sendtner, Michael
Meyer, Thomas
Ophoff, Roel A.
Staats, Kim A.
Wiedau-Pazos, Martina
Lomen-Hoerth, Catherine
Van Deerlin, Vivianna M.
Trojanowski, John Q.
Elman, Lauren
McCluskey, Leo
Basak, A. Nazli
Tunca, Ceren
Hamzeiy, Hamid
Parman, Yesim
Meitinger, Thomas
Lichtner, Peter
Radivojkov-Blagojevic, Milena
Andres, Christian R.
Maurel, Cindy
Bensimon, Gilbert
Landwehrmeyer, Bernhard
Brice, Alexis
Payan, Christine A. M.
Saker-Delye, Safaa
Duerr, Alexandra
Wood, Nicholas W.
Tittmann, Lukas
Lieb, Wolfgang
Franke, Andre
Rietschel, Marcella
Cichon, Sven
Noethen, Markus M.
Amouyel, Philippe
Tzourio, Christophe
Dartigues, Jean-Francois
Uitterlinden, Andre G.
Rivadeneira, Fernando
Estrada, Karol
Hofman, Albert
Curtis, Charles
Blauw, Hylke M.
van der Kooi, Anneke J.
de Visser, Marianne
Goris, An
Weber, Markus
Shaw, Christopher E.
Smith, Bradley N.
Pansarasa, Orietta
Cereda, Cristina
Del Bo, Roberto
Comi, Giacomo P.
D'Alfonso, Sandra
Bertolin, Cinzia
Soraru, Gianni
Mazzini, Letizia
Pensato, Viviana
Gellera, Cinzia
Tiloca, Cinzia
Ratti, Antonia
Calvo, Andrea
Moglia, Cristina
Brunetti, Maura
Arcuti, Simona
Capozzo, Rosa
Zecca, Chiara
Lunetta, Christian
Penco, Silvana
Riva, Nilo
Padovani, Alessandro
Filosto, Massimiliano
Muller, Bernard
Stuit, Robbert Jan
Blair, Ian
Zhang, Katharine
McCann, Emily P.
Fifita, Jennifer A.
Nicholson, Garth A.
Rowe, Dominic B.
Pamphlett, Roger
Kiernan, Matthew C.
Grosskreutz, Julian
Witte, Otto W.
Ringer, Thomas
Prell, Tino
Stubendorff, Beatrice
Kurth, Ingo
Huebner, Christian A.
Leigh, P. Nigel
Casale, Federico
Chio, Adrian
Beghi, Ettore
Pupillo, Elisabetta
Tortelli, Rosanna
Logroscino, Giancarlo
Powell, John
Ludolph, Albert C.
Weishaupt, Jochen H.
Robberecht, Wim
Van Damme, Philip
Franke, Lude
Pers, Tune H.
Brown, Robert H.
Glass, Jonathan D.
Landers, John E.
Hardiman, Orla
Andersen, Peter M.
Corcia, Philippe
Vourc'h, Patrick
Silani, Vincenzo
Wray, Naomi R.
Visscher, Peter M.
de Bakker, Paul I. W.
van Es, Michael A.
Pasterkamp, R. Jeroen
Lewis, Cathryn M.
Breen, Gerome
Al-Chalabi, Ammar
van den Berg, Leonard H.
Veldink, Jan H.
Title Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2016-09-01
Year available 2017
Sub-type Letter to editor, brief commentary or brief communication
DOI 10.1038/ng.3622
Open Access Status Not yet assessed
Volume 48
Issue 9
Start page 1043
End page 1048
Total pages 6
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
Abstract To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Formatted abstract
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Keyword General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy
General Chemistry
Q-Index Code CX
Q-Index Status Provisional Code
Grant ID 81030019
1084417
401162
104532
Institutional Status UQ

Document type: Journal Article
Sub-type: Letter to editor, brief commentary or brief communication
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
UQ Diamantina Institute Publications
 
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