التفاصيل البيبلوغرافية
| العنوان: |
Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis |
| المؤلفون: |
ITALSGEN Consortium, Int ALS Genomics Consortium, Bandres-Ciga, Sara, Tienari, Pentti J. |
| المساهمون: |
Department of Neurosciences, Neurologian yksikkö, Clinicum, HUS Neurocenter |
| بيانات النشر: |
Wiley |
| سنة النشر: |
2020 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
LD SCORE REGRESSION, MENDELIAN RANDOMIZATION, CHOLESTEROL HOMEOSTASIS, CARDIOVASCULAR-DISEASE, ALZHEIMERS-DISEASE, PROTECTIVE FACTOR, DYSLIPIDEMIA, BIAS, Neurosciences, Neurology and psychiatry |
| الوصف: |
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 ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| Relation: |
This work was supported by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02); by the National Institute of Neurological Disorders and Stroke; and by Merck & Co., Inc. A.J. Noyce is funded by the Barts Charity (Preventive Neurology Unit). Gibran Hemani is funded by the Wellcome Trust and the Royal Society [208806/Z/17/Z]. Andrea Calvo receives research support from Fondazione Vialli e Mauro onlus. Pentti J. Tienari received funding support from Helsinki University Hospital and the Sigrid Juselius Foundation. A. Chio receives research support from the Italian Ministry of Health (Ricerca Finalizzata RF-2010-2309849 and RF-2016-02362405), the University of Turin (Ricerca locale ex 60% 2016 and 2017), and the Joint Programme Neurodegenerative Disease Research (JPND) (BRAIN-MEND project supported by Italian Ministry of University). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013; Grant Agreement No. 259867) and support from the Target ALS Multicenter Postmortem Core and the Canadian Consortium on Neurodegeneration in Aging (ER). This study has been supported by the Italian Ministry of University under the Department of Excellence funding awarded to the 'Rita Levi Montalcini Department of Neuroscience. Bryan J. Traynor received additional support from the Center for Disease Control and Prevention, the Muscular Dystrophy Association, Microsoft Research, the Packard Center for ALS Research at Johns Hopkins, and the ALS Association.; ITALSGEN Consortium , Int ALS Genomics Consortium , Bandres-Ciga , S & Tienari , P J 2019 , ' Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis ' , Annals of Neurology , vol. 85 , no. 4 , pp. 470-481 . https://doi.org/10.1002/ana.25431; http://hdl.handle.net/10138/312662; b2859d2b-182b-4594-b7fd-3e8243680737; 000466415500003 |
| الاتاحة: |
http://hdl.handle.net/10138/312662 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| رقم الانضمام: |
edsbas.C7CC8420 |
| قاعدة البيانات: |
BASE |