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 Tc van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, William Sproviero, Ashley R Jones, Kevin P Kenna, Kristel R van EijkOliver 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, Pietro Fratta, Simon Topp, Charles Curtis, Christopher E Shaw, Bradley N Smith, P Nigel Leigh, John Powell, Cathryn M Lewis, Gerome Breen, Ammar Al-Chalabi, PARALS Registry

Research output: Contribution to journalArticlepeer-review

386 Citations (Scopus)
117 Downloads (Pure)

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 languageEnglish
Pages (from-to)1043–1048
JournalNature Genetics
Volume48
Early online date25 Jul 2016
DOIs
Publication statusPublished - Sept 2016

Fingerprint

Dive into the research topics of 'Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this