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

Wouter Van Rheenen, Aleksey Shatunov, Annelot M. Dekker, Russell L. McLaughlin, Frank P. Diekstra, Sara L. Pulit, Rick A A Van Der Spek, Urmo Võsa, Simone De Jong, Matthew R. Robinson, Jian Yang, Isabella Fogh, Perry T C Van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M. Blokhuis, William Sproviero, Ashley R. Jones, Kevin P. Kenna, Kristel R. Van Eijk & 158 others Oliver Harschnitz, Raymond D. Schellevis, William J. Brands, Jelena Medic, Androniki Menelaou, Alice Vajda, Nicola Ticozzi, Kuang Lin, Boris Rogelj, Katarina Vrabec, Metka Ravnik-Glava, Bla Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Grošelj, Stéphanie Millecamps, François Salachas, Vincent Meininger, Mamede De Carvalho, Susana Pinto, Jesus S. Mora, Ricardo Rojas-García, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E. Morrison, Pamela J. Shaw, John Hardy, Richard W. Orrell, Alan Pittman, Katie Sidle, Pietro Fratta, Andrea Malaspina, Simon Topp, Susanne Petri, Susanne Abdulla, Carsten Drepper, Michael Sendtner, Thomas Meyer, Roel A. Ophoff, Kim A. Staats, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M. Van Deerlin, John Q. Trojanowski, Lauren Elman, Leo McCluskey, A. Nazli Basak, Ceren Tunca, Hamid Hamzeiy, Yesim Parman, Thomas Meitinger, Peter Lichtner, Milena Radivojkov-Blagojevic, Christian R. Andres, Cindy Maurel, Gilbert Bensimon, Bernhard Landwehrmeyer, Alexis Brice, Christine A M Payan, Safaa Saker-Delye, Alexandra Dürr, Nicholas W. Wood, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Marcella Rietschel, Sven Cichon, Markus M. Nöthen, Philippe Amouyel, Christophe Tzourio, Jean François Dartigues, Andre G. Uitterlinden, Fernando Rivadeneira, Karol Estrada, Albert Hofman, Charles Curtis, Hylke M. Blauw, Anneke J. Van Der Kooi, Marianne De Visser, An Goris, Markus Weber, Christopher E. Shaw, Bradley N. Smith, Orietta Pansarasa, Cristina Cereda, Roberto Del Bo, Giacomo P. Comi, Sandra D'Alfonso, Cinzia Bertolin, Gianni Sorarù, Letizia Mazzini, Viviana Pensato, Cinzia Gellera, Cinzia Tiloca, Antonia Ratti, Andrea Calvo, Cristina Moglia, Maura Brunetti, Simona Arcuti, Rosa Capozzo, Chiara Zecca, Christian Lunetta, Silvana Penco, Nilo Riva, Alessandro Padovani, Massimiliano Filosto, Bernard Muller, Robbert Jan Stuit, Ian Blair, Katharine Zhang, Emily P. McCann, Jennifer A. Fifita, Garth A. Nicholson, Dominic B. Rowe, Roger Pamphlett, Matthew C. Kiernan, Julian Grosskreutz, Otto W. Witte, Thomas Ringer, Tino Prell, Beatrice Stubendorff, Ingo Kurth, Christian A. Hübner, P. Nigel Leigh, Federico Casale, Adriano Chio, Ettore Beghi, Elisabetta Pupillo, Rosanna Tortelli, Giancarlo Logroscino, John Powell, Albert C. Ludolph, Jochen H. Weishaupt, Wim Robberecht, Philip Van Damme, Lude Franke, Tune H. Pers, Robert H. Brown, Jonathan D. Glass, John E. Landers, Orla Hardiman, Peter M. Andersen, Philippe Corcia, Patrick Vourc'H, Vincenzo Silani, Naomi R. Wray, Peter M. Visscher, Paul I W De Bakker, Michael A. Van Es, R. Jeroen Pasterkamp, Cathryn M. Lewis, Gerome Breen, Ammar Al-Chalabi, Leonard H. Van Den Berg, Jan H. Veldink, Kelly Williams

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages1043-1048
Number of pages6
JournalNature Genetics
Volume48
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

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Genome-Wide Association Study
Amyotrophic Lateral Sclerosis
Genome
Chromosomes, Human, Pair 21
Single Nucleotide Polymorphism
Genes

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Van Rheenen, W., Shatunov, A., Dekker, A. M., McLaughlin, R. L., Diekstra, F. P., Pulit, S. L., ... Williams, K. (2016). Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics, 48(9), 1043-1048. https://doi.org/10.1038/ng.3622
Van Rheenen, Wouter ; Shatunov, Aleksey ; Dekker, Annelot M. ; McLaughlin, Russell L. ; Diekstra, Frank P. ; Pulit, Sara L. ; Van Der Spek, Rick A A ; Võsa, 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-Glava, Metka ; Koritnik, Bla ; Zidar, Janez ; Leonardis, Lea ; Grošelj, Leja Dolenc ; Millecamps, Stéphanie ; Salachas, François ; Meininger, Vincent ; De Carvalho, Mamede ; Pinto, Susana ; Mora, Jesus S. ; Rojas-García, 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 ; Dürr, Alexandra ; Wood, Nicholas W. ; Tittmann, Lukas ; Lieb, Wolfgang ; Franke, Andre ; Rietschel, Marcella ; Cichon, Sven ; Nöthen, Markus M. ; Amouyel, Philippe ; Tzourio, Christophe ; Dartigues, Jean François ; 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 ; Sorarù, 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 ; Hübner, Christian A. ; Nigel Leigh, P. ; Casale, Federico ; Chio, Adriano ; 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. ; Jeroen Pasterkamp, R. ; Lewis, Cathryn M. ; Breen, Gerome ; Al-Chalabi, Ammar ; Van Den Berg, Leonard H. ; Veldink, Jan H. ; Williams, Kelly. / Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. In: Nature Genetics. 2016 ; Vol. 48, No. 9. pp. 1043-1048.
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title = "Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis",
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.",
author = "{Van Rheenen}, Wouter and Aleksey Shatunov and Dekker, {Annelot M.} and McLaughlin, {Russell L.} and Diekstra, {Frank P.} and Pulit, {Sara L.} and {Van Der Spek}, {Rick A A} and Urmo V{\~o}sa and {De Jong}, Simone and Robinson, {Matthew R.} and Jian Yang and Isabella Fogh and {Van Doormaal}, {Perry T C} and Tazelaar, {Gijs H P} and Max Koppers and Blokhuis, {Anna M.} and William Sproviero and Jones, {Ashley R.} and Kenna, {Kevin P.} and {Van Eijk}, {Kristel R.} and Oliver Harschnitz and Schellevis, {Raymond D.} and Brands, {William J.} and Jelena Medic and Androniki Menelaou and Alice Vajda and Nicola Ticozzi and Kuang Lin and Boris Rogelj and Katarina Vrabec and Metka Ravnik-Glava and Bla Koritnik and Janez Zidar and Lea Leonardis and Grošelj, {Leja Dolenc} and St{\'e}phanie Millecamps and Fran{\cc}ois Salachas and Vincent Meininger and {De Carvalho}, Mamede and Susana Pinto and Mora, {Jesus S.} and Ricardo Rojas-Garc{\'i}a and Meraida Polak and Siddharthan Chandran and Shuna Colville and Robert Swingler and Morrison, {Karen E.} and Shaw, {Pamela J.} and John Hardy and Orrell, {Richard W.} and Alan Pittman and Katie Sidle and Pietro Fratta and Andrea Malaspina and Simon Topp and Susanne Petri and Susanne Abdulla and Carsten Drepper and Michael Sendtner and Thomas Meyer and Ophoff, {Roel A.} and Staats, {Kim A.} and Martina Wiedau-Pazos and Catherine Lomen-Hoerth and {Van Deerlin}, {Vivianna M.} and Trojanowski, {John Q.} and Lauren Elman and Leo McCluskey and Basak, {A. Nazli} and Ceren Tunca and Hamid Hamzeiy and Yesim Parman and Thomas Meitinger and Peter Lichtner and Milena Radivojkov-Blagojevic and Andres, {Christian R.} and Cindy Maurel and Gilbert Bensimon and Bernhard Landwehrmeyer and Alexis Brice and Payan, {Christine A M} and Safaa Saker-Delye and Alexandra D{\"u}rr and Wood, {Nicholas W.} and Lukas Tittmann and Wolfgang Lieb and Andre Franke and Marcella Rietschel and Sven Cichon and N{\"o}then, {Markus M.} and Philippe Amouyel and Christophe Tzourio and Dartigues, {Jean Fran{\cc}ois} and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Karol Estrada and Albert Hofman and Charles Curtis and Blauw, {Hylke M.} and {Van Der Kooi}, {Anneke J.} and {De Visser}, Marianne and An Goris and Markus Weber and Shaw, {Christopher E.} and Smith, {Bradley N.} and Orietta Pansarasa and Cristina Cereda and {Del Bo}, Roberto and Comi, {Giacomo P.} and Sandra D'Alfonso and Cinzia Bertolin and Gianni Sorar{\`u} and Letizia Mazzini and Viviana Pensato and Cinzia Gellera and Cinzia Tiloca and Antonia Ratti and Andrea Calvo and Cristina Moglia and Maura Brunetti and Simona Arcuti and Rosa Capozzo and Chiara Zecca and Christian Lunetta and Silvana Penco and Nilo Riva and Alessandro Padovani and Massimiliano Filosto and Bernard Muller and Stuit, {Robbert Jan} and Ian Blair and Katharine Zhang and McCann, {Emily P.} and Fifita, {Jennifer A.} and Nicholson, {Garth A.} and Rowe, {Dominic B.} and Roger Pamphlett and Kiernan, {Matthew C.} and Julian Grosskreutz and Witte, {Otto W.} and Thomas Ringer and Tino Prell and Beatrice Stubendorff and Ingo Kurth and H{\"u}bner, {Christian A.} and {Nigel Leigh}, P. and Federico Casale and Adriano Chio and Ettore Beghi and Elisabetta Pupillo and Rosanna Tortelli and Giancarlo Logroscino and John Powell and Ludolph, {Albert C.} and Weishaupt, {Jochen H.} and Wim Robberecht and {Van Damme}, Philip and Lude Franke and Pers, {Tune H.} and Brown, {Robert H.} and Glass, {Jonathan D.} and Landers, {John E.} and Orla Hardiman and Andersen, {Peter M.} and Philippe Corcia and Patrick Vourc'H and Vincenzo Silani and Wray, {Naomi R.} and Visscher, {Peter M.} and {De Bakker}, {Paul I W} and {Van Es}, {Michael A.} and {Jeroen Pasterkamp}, R. and Lewis, {Cathryn M.} and Gerome Breen and Ammar Al-Chalabi and {Van Den Berg}, {Leonard H.} and Veldink, {Jan H.} and Kelly Williams",
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month = "9",
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language = "English",
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pages = "1043--1048",
journal = "Nature Genetics",
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Van Rheenen, W, Shatunov, A, Dekker, AM, McLaughlin, RL, Diekstra, FP, Pulit, SL, Van Der Spek, RAA, Võsa, U, De Jong, S, Robinson, MR, Yang, J, Fogh, I, Van Doormaal, PTC, Tazelaar, GHP, Koppers, M, Blokhuis, AM, Sproviero, W, Jones, AR, Kenna, KP, Van Eijk, KR, Harschnitz, O, Schellevis, RD, Brands, WJ, Medic, J, Menelaou, A, Vajda, A, Ticozzi, N, Lin, K, Rogelj, B, Vrabec, K, Ravnik-Glava, M, Koritnik, B, Zidar, J, Leonardis, L, Grošelj, LD, Millecamps, S, Salachas, F, Meininger, V, De Carvalho, M, Pinto, S, Mora, JS, Rojas-García, R, Polak, M, Chandran, S, Colville, S, Swingler, R, Morrison, KE, Shaw, PJ, Hardy, J, Orrell, RW, Pittman, A, Sidle, K, Fratta, P, Malaspina, A, Topp, S, Petri, S, Abdulla, S, Drepper, C, Sendtner, M, Meyer, T, Ophoff, RA, Staats, KA, Wiedau-Pazos, M, Lomen-Hoerth, C, Van Deerlin, VM, Trojanowski, JQ, Elman, L, McCluskey, L, Basak, AN, Tunca, C, Hamzeiy, H, Parman, Y, Meitinger, T, Lichtner, P, Radivojkov-Blagojevic, M, Andres, CR, Maurel, C, Bensimon, G, Landwehrmeyer, B, Brice, A, Payan, CAM, Saker-Delye, S, Dürr, A, Wood, NW, Tittmann, L, Lieb, W, Franke, A, Rietschel, M, Cichon, S, Nöthen, MM, Amouyel, P, Tzourio, C, Dartigues, JF, Uitterlinden, AG, Rivadeneira, F, Estrada, K, Hofman, A, Curtis, C, Blauw, HM, Van Der Kooi, AJ, De Visser, M, Goris, A, Weber, M, Shaw, CE, Smith, BN, Pansarasa, O, Cereda, C, Del Bo, R, Comi, GP, D'Alfonso, S, Bertolin, C, Sorarù, G, Mazzini, L, Pensato, V, Gellera, C, Tiloca, C, Ratti, A, Calvo, A, Moglia, C, Brunetti, M, Arcuti, S, Capozzo, R, Zecca, C, Lunetta, C, Penco, S, Riva, N, Padovani, A, Filosto, M, Muller, B, Stuit, RJ, Blair, I, Zhang, K, McCann, EP, Fifita, JA, Nicholson, GA, Rowe, DB, Pamphlett, R, Kiernan, MC, Grosskreutz, J, Witte, OW, Ringer, T, Prell, T, Stubendorff, B, Kurth, I, Hübner, CA, Nigel Leigh, P, Casale, F, Chio, A, Beghi, E, Pupillo, E, Tortelli, R, Logroscino, G, Powell, J, Ludolph, AC, Weishaupt, JH, Robberecht, W, Van Damme, P, Franke, L, Pers, TH, Brown, RH, Glass, JD, Landers, JE, Hardiman, O, Andersen, PM, Corcia, P, Vourc'H, P, Silani, V, Wray, NR, Visscher, PM, De Bakker, PIW, Van Es, MA, Jeroen Pasterkamp, R, Lewis, CM, Breen, G, Al-Chalabi, A, Van Den Berg, LH, Veldink, JH & Williams, K 2016, 'Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis', Nature Genetics, vol. 48, no. 9, pp. 1043-1048. https://doi.org/10.1038/ng.3622

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; Võsa, 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-Glava, Metka; Koritnik, Bla; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; De Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, 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; Dürr, Alexandra; Wood, Nicholas W.; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean François; 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; Sorarù, 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; Hübner, Christian A.; Nigel Leigh, P.; Casale, Federico; Chio, Adriano; 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.; Jeroen Pasterkamp, R.; Lewis, Cathryn M.; Breen, Gerome; Al-Chalabi, Ammar; Van Den Berg, Leonard H.; Veldink, Jan H.; Williams, Kelly.

In: Nature Genetics, Vol. 48, No. 9, 01.09.2016, p. 1043-1048.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

AU - Van Rheenen, Wouter

AU - Shatunov, Aleksey

AU - Dekker, Annelot M.

AU - McLaughlin, Russell L.

AU - Diekstra, Frank P.

AU - Pulit, Sara L.

AU - Van Der Spek, Rick A A

AU - Võsa, Urmo

AU - De Jong, Simone

AU - Robinson, Matthew R.

AU - Yang, Jian

AU - Fogh, Isabella

AU - Van Doormaal, Perry T C

AU - Tazelaar, Gijs H P

AU - Koppers, Max

AU - Blokhuis, Anna M.

AU - Sproviero, William

AU - Jones, Ashley R.

AU - Kenna, Kevin P.

AU - Van Eijk, Kristel R.

AU - Harschnitz, Oliver

AU - Schellevis, Raymond D.

AU - Brands, William J.

AU - Medic, Jelena

AU - Menelaou, Androniki

AU - Vajda, Alice

AU - Ticozzi, Nicola

AU - Lin, Kuang

AU - Rogelj, Boris

AU - Vrabec, Katarina

AU - Ravnik-Glava, Metka

AU - Koritnik, Bla

AU - Zidar, Janez

AU - Leonardis, Lea

AU - Grošelj, Leja Dolenc

AU - Millecamps, Stéphanie

AU - Salachas, François

AU - Meininger, Vincent

AU - De Carvalho, Mamede

AU - Pinto, Susana

AU - Mora, Jesus S.

AU - Rojas-García, Ricardo

AU - Polak, Meraida

AU - Chandran, Siddharthan

AU - Colville, Shuna

AU - Swingler, Robert

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Hardy, John

AU - Orrell, Richard W.

AU - Pittman, Alan

AU - Sidle, Katie

AU - Fratta, Pietro

AU - Malaspina, Andrea

AU - Topp, Simon

AU - Petri, Susanne

AU - Abdulla, Susanne

AU - Drepper, Carsten

AU - Sendtner, Michael

AU - Meyer, Thomas

AU - Ophoff, Roel A.

AU - Staats, Kim A.

AU - Wiedau-Pazos, Martina

AU - Lomen-Hoerth, Catherine

AU - Van Deerlin, Vivianna M.

AU - Trojanowski, John Q.

AU - Elman, Lauren

AU - McCluskey, Leo

AU - Basak, A. Nazli

AU - Tunca, Ceren

AU - Hamzeiy, Hamid

AU - Parman, Yesim

AU - Meitinger, Thomas

AU - Lichtner, Peter

AU - Radivojkov-Blagojevic, Milena

AU - Andres, Christian R.

AU - Maurel, Cindy

AU - Bensimon, Gilbert

AU - Landwehrmeyer, Bernhard

AU - Brice, Alexis

AU - Payan, Christine A M

AU - Saker-Delye, Safaa

AU - Dürr, Alexandra

AU - Wood, Nicholas W.

AU - Tittmann, Lukas

AU - Lieb, Wolfgang

AU - Franke, Andre

AU - Rietschel, Marcella

AU - Cichon, Sven

AU - Nöthen, Markus M.

AU - Amouyel, Philippe

AU - Tzourio, Christophe

AU - Dartigues, Jean François

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Estrada, Karol

AU - Hofman, Albert

AU - Curtis, Charles

AU - Blauw, Hylke M.

AU - Van Der Kooi, Anneke J.

AU - De Visser, Marianne

AU - Goris, An

AU - Weber, Markus

AU - Shaw, Christopher E.

AU - Smith, Bradley N.

AU - Pansarasa, Orietta

AU - Cereda, Cristina

AU - Del Bo, Roberto

AU - Comi, Giacomo P.

AU - D'Alfonso, Sandra

AU - Bertolin, Cinzia

AU - Sorarù, Gianni

AU - Mazzini, Letizia

AU - Pensato, Viviana

AU - Gellera, Cinzia

AU - Tiloca, Cinzia

AU - Ratti, Antonia

AU - Calvo, Andrea

AU - Moglia, Cristina

AU - Brunetti, Maura

AU - Arcuti, Simona

AU - Capozzo, Rosa

AU - Zecca, Chiara

AU - Lunetta, Christian

AU - Penco, Silvana

AU - Riva, Nilo

AU - Padovani, Alessandro

AU - Filosto, Massimiliano

AU - Muller, Bernard

AU - Stuit, Robbert Jan

AU - Blair, Ian

AU - Zhang, Katharine

AU - McCann, Emily P.

AU - Fifita, Jennifer A.

AU - Nicholson, Garth A.

AU - Rowe, Dominic B.

AU - Pamphlett, Roger

AU - Kiernan, Matthew C.

AU - Grosskreutz, Julian

AU - Witte, Otto W.

AU - Ringer, Thomas

AU - Prell, Tino

AU - Stubendorff, Beatrice

AU - Kurth, Ingo

AU - Hübner, Christian A.

AU - Nigel Leigh, P.

AU - Casale, Federico

AU - Chio, Adriano

AU - Beghi, Ettore

AU - Pupillo, Elisabetta

AU - Tortelli, Rosanna

AU - Logroscino, Giancarlo

AU - Powell, John

AU - Ludolph, Albert C.

AU - Weishaupt, Jochen H.

AU - Robberecht, Wim

AU - Van Damme, Philip

AU - Franke, Lude

AU - Pers, Tune H.

AU - Brown, Robert H.

AU - Glass, Jonathan D.

AU - Landers, John E.

AU - Hardiman, Orla

AU - Andersen, Peter M.

AU - Corcia, Philippe

AU - Vourc'H, Patrick

AU - Silani, Vincenzo

AU - Wray, Naomi R.

AU - Visscher, Peter M.

AU - De Bakker, Paul I W

AU - Van Es, Michael A.

AU - Jeroen Pasterkamp, R.

AU - Lewis, Cathryn M.

AU - Breen, Gerome

AU - Al-Chalabi, Ammar

AU - Van Den Berg, Leonard H.

AU - Veldink, Jan H.

AU - Williams, Kelly

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84979596905&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/nhmrc/1083187

UR - http://purl.org/au-research/grants/nhmrc/1078901

UR - http://purl.org/au-research/grants/nhmrc/1078037

UR - http://purl.org/au-research/grants/nhmrc/1048853

UR - http://purl.org/au-research/grants/nhmrc/1050218

U2 - 10.1038/ng.3622

DO - 10.1038/ng.3622

M3 - Article

VL - 48

SP - 1043

EP - 1048

JO - Nature Genetics

T2 - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -

Van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics. 2016 Sep 1;48(9):1043-1048. https://doi.org/10.1038/ng.3622