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Ann Neurol. 2019 Apr;85(4):470-481. doi: 10.1002/ana.25431. Epub 2019 Mar 13.

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis.

Collaborators (157)

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, 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, 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.

Author information

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain.
Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.
Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London, United Kingdom.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD.
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
ALS Center, Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy.
Department of Neurology, Helsinki University Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Genetics and Pharmacogenomics, Merck Research Laboratories, Merck & Co., Inc., West Point, PA.
Data Tecnica International, Glen Echo, MD.
Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy.
Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
Department of Neurology, Johns Hopkins University, Baltimore, MD.



To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS).


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.


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.


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.

[Available on 2020-04-01]

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