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Nature Research, Nature Genetics, 9(48), p. 1043-1048

DOI: 10.1038/ng.3622



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

Journal article published in 2016 by Rick A. A. van der Spek, Anneke J. van der Kooi, Leonard H. van den Berg, Perry Tc C. van Doormaal, Kristel R. van Eijk, Mamede de Carvalho, Marianne de Visser, Paul I. W. de Bakker, Michael A. van Es, W. van Rheenen, Simone de Jong, Wouter Van Rheenen, Annelot M. Dekker, Russell L. Mclaughlin ORCID, R. A. A. Van Der Spek and other authors.
This paper is available in a repository.
This paper is available in a repository.

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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. ; 6 page(s)