期刊
NATURE GENETICS
卷 48, 期 9, 页码 1043-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.3622
关键词
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资金
- governmental and charitable bodies
- Economic and Social Research Council [ES/L008238/1] Funding Source: researchfish
- Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish
- Medical Research Council [MR/M008606/1, MC_G1000733, MC_G0901330, G0900688, G0600974, MR/K000039/1, G0901254, MR/L501529/1] Funding Source: researchfish
- Medical Research Foundation [MRF-060-0003-RG-SMITH] Funding Source: researchfish
- Motor Neurone Disease Association [McLaughlin/Oct15/957-799, Jones/Oct15/958-799, Malaspina/Apr13/817-791, Fratta/Jan15/946-795] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10064, NF-SI-0512-10082, NF-SI-0507-10376] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Pers Group] Funding Source: researchfish
- Parkinson's UK [G-1107] Funding Source: researchfish
- ESRC [ES/L008238/1] Funding Source: UKRI
- MRC [MR/M008606/1, MC_G1000733, G0900688, MR/K000039/1, MC_G0901330, G0600974, G0901254] Funding Source: UKRI
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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