Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Issue 4 (13th March 2019)

• Record Type: Journal Article
• Authors: Bandres‐Ciga, Sara; Noyce, Alastair J.; Hemani, Gibran; Nicolas, Aude; Calvo, Andrea; Mora, Gabriele; Tienari, Pentti J.; Stone, David J.; Nalls, Mike A.; Singleton, Andrew B.; Chiò, Adriano; Traynor, Bryan J.
• Other Names: Arosio Alessandro investigator.; Barberis Marco investigator.; Bartolomei Ilaria investigator.; Battistini Stefania investigator.; Benigni Michele investigator.; Borghero Giuseppe investigator.; Brunetti Maura investigator.; Calvo Andrea investigator.; Cammarosano Stefania investigator.; Cannas Antonino investigator.; Canosa Antonio investigator.; Capasso Margherita investigator.; Caponnetto Claudia investigator.; Caredda Carla investigator.; Carrera Paola investigator.; Casale Federico investigator.; Cavallaro Sebastiano investigator.; Chiò Adriano investigator.; Colletti Tiziana investigator.; Conforti Francesca L. investigator.; Conte Amelia investigator.; Corrado Lucia investigator.; Costantino Emanuela investigator.; D'Alfonso Sandra investigator.; Fasano Antonio investigator.; Femiano Cinzia investigator.; Ferrarese Carlo investigator.; Fini Nicola investigator.; Floris Gianluca investigator.; Fuda Giuseppe investigator.; Giannini Fabio investigator.; Grassano Maurizio investigator.; Ilardi Antonio investigator.; La Bella Vincenzo investigator.; Lattante Serena investigator.; Logroscino Giancarlo investigator.; Logullo Francesco O. investigator.; Loi Daniela investigator.; Lunetta Christian investigator.; Mancardi Gianluigi investigator.; Mandich Paola investigator.; Mandrioli Jessica investigator.; Manera Umberto investigator.; Marangi Giuseppe investigator.; Marinou Kalliopi investigator.; Marrali Giuseppe investigator.; Marrosu Maria Giovanna investigator.; Mazzini Letizia investigator.; Melis Maurizio investigator.; Messina Sonia investigator.; Moglia Cristina investigator.; Monsurro Maria Rosaria investigator.; Mora Gabriele investigator.; Mosca Lorena investigator.; Occhineri Patrizia investigator.; Origone Paola investigator.; Pani Carla investigator.; Penco Silvana investigator.; Petrucci Antonio investigator.; Piccirillo Giovanni investigator.; Pirisi Angelo investigator.; Pisano Fabrizio investigator.; Pugliatti Maura investigator.; Restagno Gabriella investigator.; Ricci Claudia investigator.; Rita Murru Maria investigator.; Riva Nilo investigator.; Sabatelli Mario investigator.; Salvi Fabrizio investigator.; Santarelli Marialuisa investigator.; Sideri Riccardo investigator.; Simone Isabella investigator.; Spataro Rossella investigator.; Tanel Raffaella investigator.; Tedeschi Gioacchino investigator.; Tranquilli Stefania investigator.; Tremolizzo Lucio investigator.; Trojsi Francesca investigator.; Volanti Paolo investigator.; Zollino Marcella investigator.; Abramzon Yevgeniya investigator.; Arepalli Sampath investigator.; Baloh Robert H. investigator.; Bowser Robert investigator.; Brady Christopher B. investigator.; Brice Alexis investigator.; Broach James investigator.; Campbell Roy H. investigator.; Camu William investigator.; Chia Ruth investigator.; Chiò Adriano investigator.; Cooper‐Knock John investigator.; Cusi Daniele investigator.; Ding Jinhui investigator.; Drepper Carsten investigator.; Drory Vivian E. investigator.; Dunckley Travis L. investigator.; Eicher John D. investigator.; Faghri Faraz investigator.; Feldman Eva investigator.; Kay Floeter Mary investigator.; Fratta Pietro investigator.; Geiger Joshua T. investigator.; Gerhard Glenn investigator.; Gibbs J. Raphael investigator.; Gibson Summer B. investigator.; Glass Jonathan D. investigator.; Hardy John investigator.; Harms Matthew B. investigator.; Heiman‐Patterson Terry D. investigator.; Hernandez Dena G. investigator.; Jansson Lilja investigator.; Kamel Freya investigator.; Kirby Janine investigator.; Kowall Neil W. investigator.; Laaksovirta Hannu investigator.; Landi Francesco investigator.; Le Ber Isabelle investigator.; Lumbroso Serge investigator.; MacGowan Daniel J.L. investigator.; Maragakis Nicholas J. investigator.; Mouzat Kevin investigator.; Murphy Natalie A. investigator.; Myllykangas Liisa investigator.; Nalls Mike A. investigator.; Nicolas Aude investigator.; Orrell Richard W. investigator.; Ostrow Lyle W. investigator.; Pamphlett Roger investigator.; Pickering‐Brown Stuart investigator.; Pioro Erik investigator.; Pliner Hannah A. investigator.; Pulst Stefan M. investigator.; Ravits John M. investigator.; Renton Alan E. investigator.; Rivera Alberto investigator.; Robbrecht Wim investigator.; Rogaeva Ekaterina investigator.; Rollinson Sara investigator.; Rothstein Jeffrey D. investigator.; Salvi Erika investigator.; Scholz Sonja W. investigator.; Sendtner Michael investigator.; Shaw Pamela J. investigator.; Sidle Katie C. investigator.; Simmons Zachary investigator.; Singleton Andrew B. investigator.; Stone David C. investigator.; Sulkava Raimo investigator.; Tienari Pentti J. investigator.; Traynor Bryan J. investigator.; Trojanowski John Q. investigator.; Troncoso Juan C. investigator.; Van Damme Philip investigator.; Van Deerlin Vivianna M. investigator.; Van Den Bosch Ludo investigator.; Zinman Lorne investigator.;
• Is Part Of: Annals of neurology. Volume 85:Issue 4(2019)
• Page Start: 470
• Page End: 481
• Publication Date: 2019-03-13
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.25431
• Languages: English
• ISSNs: 0364-5134

Abstract

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