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

• Verfasst von: Van Rheenen, Wouter [VerfasserIn]
• Verfasst von: Rietschel, Marcella [VerfasserIn]
• Verfasst von: Nöthen, Markus Maria [VerfasserIn]
• Verfasst von: Weishaupt, Jochen H. [VerfasserIn]
• Titel: Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
• Verf.angabe: Wouter van Rheenen, Marcella Rietschel, Marcus M Nöthen, Jochen H Weishaupt [und 175 weitere]
• E-Jahr: 2016
• Jahr: 25 July 2016
• Umfang: 8 S.
• Fussnoten: Gesehen am 21.01.2019
• Titel Quelle: Enthalten in: Nature genetics
• Ort Quelle: London : Macmillan Publishers Limited, part of Springer Nature, 1992
• Jahr Quelle: 2016
• Band/Heft Quelle: 48(2016), 9, Seite 1043-1048
• ISSN Quelle: 1546-1718
• DOI: doi:10.1038/ng.3622
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1586426060

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.