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

TitelGenome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
MedientypJournal Article
Jahr der Veröffentlichung2016
Autorenvan Rheenen W, Shatunov A, Dekker AM, et al.
Corporate AuthorsPARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group
JournalNat Genet
Volume48
Ausgabe9
Pagination1043-8
Datum der Veröffentlichung2016 09
ISSN1546-1718
SchlüsselwörterAmyotrophic Lateral Sclerosis, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Munc18 Proteins, Mutation, Myelin Proteins, Netherlands, Proteins
Zusammenfassung

<p>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.</p>

DOI10.1038/ng.3622
Alternate JournalNat. Genet.
PubMed ID27455348
PubMed Central IDPMC5556360
Grant ListP01 AG032953 / AG / NIA NIH HHS / United States
G0901254 / / Medical Research Council / United Kingdom
MR/K000039/1 / / Medical Research Council / United Kingdom
MC_G1000733 / / Medical Research Council / United Kingdom
MR/L501529/1 / / Medical Research Council / United Kingdom
P01 AG017586 / AG / NIA NIH HHS / United States
MC_G0901330 / / Medical Research Council / United Kingdom
G0600974 / / Medical Research Council / United Kingdom
MR/M008606/1 / / Medical Research Council / United Kingdom
MALASPINA/APR13/817-791 / / Motor Neurone Disease Association / United Kingdom
R01 NS073873 / NS / NINDS NIH HHS / United States
G0900688 / / Medical Research Council / United Kingdom
G-1107 / / Parkinson's UK / United Kingdom
/ / Wellcome Trust / United Kingdom