Abstract

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 (https://lng-nia.shinyapps.io/mrshiny) 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.

Original languageEnglish
Pages (from-to)470-481
Number of pages12
JournalAnnals of Neurology
Volume85
Issue number4
DOIs
StatePublished - 1 Apr 2019

Funding

FundersFunder number
Canadian Consortium on Neurodegeneration in Aging
European Community’s Health Seventh Framework Programme
FP7/2007
Fondazione Vialli e Mauro onlus
Helsinki University Hospital
Italian Ministry of Health
Italian Ministry of University
Sigrid Jus?lius Foundation
Wellcome Trust Case Control Consortium
National Institutes of Health
Centers for Disease Control and Prevention
National Institute on AgingZIAAG000957, Z01-AG000949-02
National Institute of Neurological Disorders and Stroke
Amyotrophic Lateral Sclerosis Association
Merck
Muscular Dystrophy Association
Microsoft Research
Helsingin ja Uudenmaan Sairaanhoitopiiri
Wellcome Trust
Seventh Framework Programme259867
EU Joint Programme – Neurodegenerative Disease Research
Consortium canadien en neurodégénérescence associée au vieillissement
Royal Society208806/Z/17/Z
Ministero della SaluteRF-2010-2309849, RF-2016-02362405
Ministero dell’Istruzione, dell’Università e della Ricerca
Seventh Framework Programme
Sigrid Juséliuksen Säätiö
Università degli Studi di Torino

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