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

van Rheenen, W; Shatunov, A; Dekker, AM; McLaughlin, RL; Diekstra, FP; Pulit, SL; van der Spek, RAA; ... Veldink, JH; + view all (2016) Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nature Genetics , 48 (9) pp. 1043-1048. 10.1038/ng.3622. Green open access

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Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genomesequenced 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.

Type: Article
Title: Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ng.3622
Publisher version: http://doi.org/10.1038/ng.3622
Language: English
Additional information: © 2016 Nature America, Inc. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, FRONTOTEMPORAL DEMENTIA, HEXANUCLEOTIDE REPEAT, ALS, SUSCEPTIBILITY, POPULATION, EFFICIENT, PATHWAYS, PITFALLS, SEQUENCE, COMPLEX
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1506189
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