Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

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.

Metadata

Item Type:	Article
Authors/Creators:	Bandres‐Ciga, S Noyce, AJ Hemani, G Nicolas, A Calvo, A Mora, G Arosio, A Barberis, M Bartolomei, I Battistini, S Benigni, M Borghero, G Brunetti, M Calvo, A Cammarosano, S Cannas, A Canosa, A Capasso, M Caponnetto, C Caredda, C Carrera, P Casale, F Cavallaro, S Chiò, A Colletti, T Conforti, FL Conte, A Corrado, L Costantino, E D'Alfonso, S Fasano, A Femiano, C Ferrarese, C Fini, N Floris, G Fuda, G Giannini, F Grassano, M Ilardi, A La Bella, V Lattante, S Logroscino, G Logullo, FO Loi, D Lunetta, C Mancardi, G Mandich, P Mandrioli, J Manera, U Marangi, G Marinou, K Marrali, G Marrosu, MG Mazzini, L Melis, M Messina, S Moglia, C Monsurro, MR Mora, G Mosca, L Occhineri, P Origone, P Pani, C Penco, S Petrucci, A Piccirillo, G Pirisi, A Pisano, F Pugliatti, M Restagno, G Ricci, C Rita Murru, M Riva, N Sabatelli, M Salvi, F Santarelli, M Sideri, R Simone, I Spataro, R Tanel, R Tedeschi, G Tranquilli, S Tremolizzo, L Trojsi, F Volanti, P Zollino, M Abramzon, Y Arepalli, S Baloh, RH Bowser, R Brady, CB Brice, A Broach, J Campbell, RH Camu, W Chia, R Chiò, A Cooper‐Knock, J Cusi, D Ding, J Drepper, C Drory, VE Dunckley, TL Eicher, JD Faghri, F Feldman, E Kay Floeter, M Fratta, P Geiger, JT Gerhard, G Gibbs, JR Gibson, SB Glass, JD Hardy, J Harms, MB Heiman‐Patterson, TD Hernandez, DG Jansson, L Kamel, F Kirby, J https://orcid.org/0000-0002-7468-5917 Kowall, NW Laaksovirta, H Landi, F Le Ber, I Lumbroso, S MacGowan, DJL Maragakis, NJ Mouzat, K Murphy, NA Myllykangas, L Nalls, MA Nicolas, A Orrell, RW Ostrow, LW Pamphlett, R Pickering‐Brown, S Pioro, E Pliner, HA Pulst, SM Ravits, JM Renton, AE Rivera, A Robbrecht, W Rogaeva, E Rollinson, S Rothstein, JD Salvi, E Scholz, SW Sendtner, M Shaw, PJ https://orcid.org/0000-0002-8925-2567 Sidle, KC Simmons, Z Singleton, AB Stone, DC Sulkava, R Tienari, PJ Traynor, BJ Trojanowski, JQ Troncoso, JC Van Damme, P Van Deerlin, VM Van Den Bosch, L Zinman, L Tienari, PJ Stone, DJ Nalls, MA Singleton, AB Chiò, A Traynor, BJ
Copyright, Publisher and Additional Information:	© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Dates:	Accepted: 1 February 2019 Published (online): 5 February 2019 Published: April 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number MEDICAL RESEARCH COUNCIL MR/K003771/1 EUROPEAN COMMISSION - FP6/FP7 EUROMOTOR - 259867
Depositing User:	Symplectic Sheffield
Date Deposited:	07 Oct 2020 11:43
Last Modified:	07 Oct 2020 11:43
Status:	Published
Publisher:	Wiley
Refereed:	Yes
Identification Number:	10.1002/ana.25431
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:166378

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Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

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