期刊
ANNALS OF NEUROLOGY
卷 85, 期 4, 页码 470-481出版社
WILEY
DOI: 10.1002/ana.25431
关键词
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资金
- Intramural Research Program of the NIH, National Institute on Aging [Z01-AG000949-02]
- National Institute of Neurological Disorders and Stroke
- Merck Co., Inc.
- Barts Charity (Preventive Neurology Unit)
- Wellcome Trust
- Royal Society [208806/Z/17/Z]
- Fondazione Vialli e Mauro onlus
- Helsinki University Hospital
- Sigrid Juselius Foundation
- Italian Ministry of Health [RF-2010-2309849, RF-2016-02362405]
- University of Turin
- Joint Programme Neurodegenerative Disease Research (JPND) (Italian Ministry of University)
- European Community's Health Seventh Framework Programme (FP7/2007-2013) [259867]
- Target ALS Multicenter Postmortem Core
- Canadian Consortium on Neurodegeneration in Aging
- Italian Ministry of University under the Department of Excellence funding
- Center for Disease Control and Prevention
- Muscular Dystrophy Association
- Microsoft Research
- Packard Center for ALS Research at Johns Hopkins
- ALS Association
- NATIONAL INSTITUTE ON AGING [ZIAAG000933, ZIAAG000957] Funding Source: NIH RePORTER
- MRC [G0701075, UKDRI-1009, MR/K01417X/1, MR/N026004/1, G0901254] Funding Source: UKRI
Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation Here, we have developed a public resource () which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481
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