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Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Research output: Contribution to journalArticle

  • ITALSGEN Consortium
Original languageEnglish
Pages (from-to)470-481
Number of pages12
JournalAnnals of Neurology
Volume85
Issue number4
Early online date13 Mar 2019
DOIs
DateAccepted/In press - 1 Feb 2019
DateE-pub ahead of print - 13 Mar 2019
DatePublished (current) - 5 Apr 2019

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.

Additional information

© 2019 American Neurological Association.

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    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via Wiley at https://doi.org/10.1002/ana.25431 . Please refer to any applicable terms of use of the publisher.

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    Embargo ends: 13/03/20

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