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

Publication

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

Journal Paper/Review - Jul 25, 2016

Zhang Katharine, Arcuti Simona, Brunetti Maura, Moglia Cristina, Calvo Andrea, Ratti Antonia, Tiloca Cinzia, Gellera Cinzia, Pensato Viviana, Mazzini Letizia, Capozzo Rosa, Zecca Chiara, Blair Ian, Stuit Robbert Jan, Muller Bernard, Filosto Massimiliano, Padovani Alessandro, Riva Nilo, Penco Silvana, Lunetta Christian, Sorarù Gianni, Bertolin Cinzia, Blauw Hylke M, Curtis Charles, Hofman Albert, Estrada Karol, Rivadeneira Fernando, Uitterlinden André G, Dartigues Jean-François, Tzourio Christophe, Amouyel Philippe, van der Kooi Anneke J, de Visser Marianne, D'Alfonso Sandra, Comi Giacomo P, Del Bo Roberto, Cereda Cristina, Pansarasa Orietta, Smith Bradley N, Shaw Christopher E, Weber Markus, Goris An, Nöthen Markus M, McCann Emily P, Veldink Jan H, Corcia Philippe, Andersen Peter M, Hardiman Orla, Landers John E, Glass Jonathan D, Brown Robert H, Pers Tune H, Franke Lude, Van Damme Philip, Vourc'h Patrick, Silani Vincenzo, van den Berg Leonard H, Al-Chalabi Ammar, Breen Gerome, Lewis Cathryn M, Pasterkamp R Jeroen, van Es Michael A, de Bakker Paul I W, Visscher Peter M, Wray Naomi R, Robberecht Wim, Weishaupt Jochen H, Stubendorff Beatrice, Prell Tino, Ringer Thomas, Witte Otto W, Grosskreutz Julian, Kiernan Matthew C, Pamphlett Roger, Rowe Dominic B, Nicholson Garth A, Kurth Ingo, Hübner Christian A, Ludolph Albert C, Powell John, Logroscino Giancarlo, Tortelli Rosanna, Pupillo Elisabetta, Beghi Ettore, Chio Adriano, Casale Federico, Leigh P Nigel, Fifita Jennifer A, Chandran Siddharthan, Koritnik Blaž, Ravnik-Glavač Metka, Vrabec Katarina, Rogelj Boris, Lin Kuang, Ticozzi Nicola, Vajda Alice, Menelaou Androniki, Medic Jelena, Zidar Janez, Leonardis Lea, Polak Meraida, Rojas-García Ricardo, Mora Jesus S, Pinto Susana, de Carvalho Mamede, Meininger Vincent, Salachas François, Millecamps Stéphanie, Grošelj Leja Dolenc, Brands William J, Schellevis Raymond D, Robinson Matthew R, de Jong Simone, Võsa Urmo, van der Spek Rick A A, Pulit Sara L, Diekstra Frank P, McLaughlin Russell L, Dekker Annelot M, Shatunov Aleksey, Yang Jian, Fogh Isabella, Harschnitz Oliver, van Eijk Kristel R, Kenna Kevin P, Jones Ashley R, Sproviero William, Blokhuis Anna M, Koppers Max, Tazelaar Gijs H P, van Doormaal Perry Tc, van Rheenen Wouter, Colville Shuna, Cichon Sven, Maurel Cindy, Andres Christian R, Radivojkov-Blagojevic Milena, Lichtner Peter, Meitinger Thomas, Parman Yesim, Hamzeiy Hamid, Tunca Ceren, Basak A Nazli, Bensimon Gilbert, Landwehrmeyer Bernhard, Rietschel Marcella, Franke Andre, Lieb Wolfgang, Tittmann Lukas, Wood Nicholas W, Dürr Alexandra, Saker-Delye Safaa, Payan Christine A M, Brice Alexis, McCluskey Leo, Elman Lauren, Topp Simon, Malaspina Andrea, Fratta Pietro, Sidle Katie, Pittman Alan, Orrell Richard W, Hardy John, Shaw Pamela J, Morrison Karen E, Petri Susanne, Abdulla Susanne, Trojanowski John Q, Van Deerlin Vivianna M, Lomen-Hoerth Catherine, Wiedau-Pazos Martina, Staats Kim A, Ophoff Roel A, Meyer Thomas, Sendtner Michael, Drepper Carsten, Swingler Robert

Citation

Zhang K, Arcuti S, Brunetti M, Moglia C, Calvo A, Ratti A, Tiloca C, Gellera C, Pensato V, Mazzini L, Capozzo R, Zecca C, Blair I, Stuit R, Muller B, Filosto M, Padovani A, Riva N, Penco S, Lunetta C, Sorarù G, Bertolin C, Blauw H, Curtis C, Hofman A, Estrada K, Rivadeneira F, Uitterlinden A, Dartigues J, Tzourio C, Amouyel P, van der Kooi A, de Visser M, D'Alfonso S, Comi G, Del Bo R, Cereda C, Pansarasa O, Smith B, Shaw C, Weber M, Goris A, Nöthen M, McCann E, Veldink J, Corcia P, Andersen P, Hardiman O, Landers J, Glass J, Brown R, Pers T, Franke L, Van Damme P, Vourc'h P, Silani V, van den Berg L, Al-Chalabi A, Breen G, Lewis C, Pasterkamp R, van Es M, de Bakker P, Visscher P, Wray N, Robberecht W, Weishaupt J, Stubendorff B, Prell T, Ringer T, Witte O, Grosskreutz J, Kiernan M, Pamphlett R, Rowe D, Nicholson G, Kurth I, Hübner C, Ludolph A, Powell J, Logroscino G, Tortelli R, Pupillo E, Beghi E, Chio A, Casale F, Leigh P, Fifita J, Chandran S, Koritnik B, Ravnik-Glavač M, Vrabec K, Rogelj B, Lin K, Ticozzi N, Vajda A, Menelaou A, Medic J, Zidar J, Leonardis L, Polak M, Rojas-García R, Mora J, Pinto S, de Carvalho M, Meininger V, Salachas F, Millecamps S, Grošelj L, Brands W, Schellevis R, Robinson M, de Jong S, Võsa U, van der Spek R, Pulit S, Diekstra F, McLaughlin R, Dekker A, Shatunov A, Yang J, Fogh I, Harschnitz O, van Eijk K, Kenna K, Jones A, Sproviero W, Blokhuis A, Koppers M, Tazelaar G, van Doormaal P, van Rheenen W, Colville S, Cichon S, Maurel C, Andres C, Radivojkov-Blagojevic M, Lichtner P, Meitinger T, Parman Y, Hamzeiy H, Tunca C, Basak A, Bensimon G, Landwehrmeyer B, Rietschel M, Franke A, Lieb W, Tittmann L, Wood N, Dürr A, Saker-Delye S, Payan C, Brice A, McCluskey L, Elman L, Topp S, Malaspina A, Fratta P, Sidle K, Pittman A, Orrell R, Hardy J, Shaw P, Morrison K, Petri S, Abdulla S, Trojanowski J, Van Deerlin V, Lomen-Hoerth C, Wiedau-Pazos M, Staats K, Ophoff R, Meyer T, Sendtner M, Drepper C, Swingler R. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet 2016; 48:1043-8.

Type

Journal Paper/Review (English)

Journal

Nat Genet 2016; 48

Publication Date

Jul 25, 2016

Issn Electronic

1546-1718

Pages

1043-8

Brief description/objective

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.