The University of Southampton
University of Southampton Institutional Repository

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

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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.
1061-4036
1043-1048
van Rheenen, Wouter
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Shatunov, Aleksey
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Dekker, Annelot M.
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McLaughlin, Russell L.
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Diekstra, Frank P.
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Pulit, Sara L.
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van der Spek, Rick A.A.
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Võsa, Urmo
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de Jong, Simone
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Robinson, Matthew R.
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Yang, Jian
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Fogh, Isabella
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van Doormaal, Perry T.C.
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Sproviero, William
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van Eijk, Kristel R.
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Brands, William J.
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Medic, Jelena
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Shaw, Pamela J.
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Hardy, John
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Meyer, Thomas
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Radivojkov-Blagojevic, Milena
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Andres, Christian R
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Maurel, Cindy
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Bensimon, Gilbert
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Landwehrmeyer, Bernhard
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Wood, Nicholas W.
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van Rheenen, Wouter
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de Carvalho, Mamede
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Pittman, Alan
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Al-Chalabi, Ammar
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van Rheenen, Wouter, Shatunov, Aleksey and Dekker, Annelot M. et al. (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).

Record type: Article

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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Accepted/In Press date: 20 June 2016
e-pub ahead of print date: 25 July 2016
Published date: 1 September 2016
Organisations: Faculty of Medicine

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Local EPrints ID: 402882
URI: http://eprints.soton.ac.uk/id/eprint/402882
ISSN: 1061-4036
PURE UUID: 84cd0188-8edd-44d2-823a-843b7c861838
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 15 Nov 2016 11:53
Last modified: 07 Oct 2020 02:09

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Contributors

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

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