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

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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 Tc van Doormaal ; Gijs H P Tazelaar ; Max Koppers ; Anna M Blokhuis ; William Sproviero ; Ashley R Jones ; Kevin P Kenna ; Kristel R van Eijk ; Oliver Harschnitz ; Raymond D Schellevis ; William J Brands ; Jelena Medic ; Androniki Menelaou ; Alice Vajda ; Nicola Ticozzi ; Kuang Lin ; Boris Rogelj ; Katarina Vrabec ; Metka Ravnik-Glavač ; Blaž 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 ; PARALS Registry

Original languageEnglish
JournalNature Genetics
Early online date25 Jul 2016
DOIs
StateE-pub ahead of print - 25 Jul 2016

King's Authors

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.

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