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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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.
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Publication status
- Published
Journal
Nature GeneticsISSN
1061-4036Publisher
Nature Publishing GroupExternal DOI
Issue
9Volume
48Page range
1043-1048Department affiliated with
- BSMS Neuroscience Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2017-01-30Usage metrics
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