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.
| Original language | English |
|---|---|
| Pages (from-to) | 1043-1048 |
| Number of pages | 6 |
| Journal | Nature Genetics |
| Volume | 48 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Sep 2016 |
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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 journal › Article › peer-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
C2 - 27455348
AN - SCOPUS:84979596905
VL - 48
SP - 1043
EP - 1048
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 9
ER -