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 Vosa, Simone de Jong, Matthew R. Robinson, Jian Yang, Isabella Fogh, Perry T. C. 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-Glavac, Blazi Koritnik, Janez Zidar, Lea Leonardis, Leja Dolenc Groselj, Stephanie Millecamps, Francois Salachas, Vincent Meininger, Mamede de Carvalho, Susana Pinto, Jesus S. Mora, Ricardo Rojas-Garcia, Meraida Polak, Siddharthan Chandran, Shuna Colville, Robert Swingler, Karen E. Morrison, Pamela J. Shaw, John Hardy, Lude Franke, PARALS Registry, SLALOM Grp, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Grp

Research output: Contribution to journalArticleAcademicpeer-review

212 Citations (Scopus)

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)1043-1050
Number of pages8
JournalNature Genetics
Volume48
Issue number9
DOIs
Publication statusPublished - Sep-2016

Keywords

  • FRONTOTEMPORAL DEMENTIA
  • HEXANUCLEOTIDE REPEAT
  • ALS
  • SUSCEPTIBILITY
  • POPULATION
  • EFFICIENT
  • PATHWAYS
  • PITFALLS
  • SEQUENCE
  • COMPLEX

Cite this