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;00:1–12.

Original languageEnglish
JournalAnnals of Neurology
DOIs
Publication statusPublished - Jan 1 2019

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Amyotrophic Lateral Sclerosis
Genome-Wide Association Study
Linkage Disequilibrium
Random Allocation
Smoking
Psychomotor Agitation
Bayes Theorem
Hyperlipidemias
Causality
Multivariate Analysis
Randomized Controlled Trials
Light

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. / The ITALSGEN Consortium; The International ALS Genomics Consortium.

In: Annals of Neurology, 01.01.2019.

Research output: Contribution to journalArticle

The ITALSGEN Consortium ; The International ALS Genomics Consortium. / Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. In: Annals of Neurology. 2019.
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title = "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. Ann Neurol 2019;00:1–12.",
author = "{The ITALSGEN Consortium} and {The International ALS Genomics Consortium} and Sara Bandres-Ciga and Noyce, {Alastair J.} and Gibran Hemani and Aude Nicolas and Andrea Calvo and Gabriele Mora and Alessandro Arosio and Marco Barberis and Ilaria Bartolomei and Stefania Battistini and Michele Benigni and Giuseppe Borghero and Maura Brunetti and Andrea Calvo and Stefania Cammarosano and Antonino Cannas and Antonio Canosa and Margherita Capasso and Claudia Caponnetto and Carla Caredda and Paola Carrera and Federico Casale and Sebastiano Cavallaro and Adriano Chi{\`o} and Tiziana Colletti and Conforti, {Francesca L.} and Amelia Conte and Lucia Corrado and Emanuela Costantino and Sandra D'Alfonso and Antonio Fasano and Cinzia Femiano and Carlo Ferrarese and Nicola Fini and Gianluca Floris and Giuseppe Fuda and Fabio Giannini and Gianluigi Mancardi and Paola Mandich and Sonia Messina and Gabriele Mora and Fabrizio Pisano and Claudia Ricci and Nilo Riva and Mario Sabatelli and Fabrizio Salvi and Riccardo Sideri and Rossella Spataro and Paolo Volanti and Marcella Zollino",
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AU - The ITALSGEN Consortium

AU - The International ALS Genomics Consortium

AU - Bandres-Ciga, Sara

AU - Noyce, Alastair J.

AU - Hemani, Gibran

AU - Nicolas, Aude

AU - Calvo, Andrea

AU - Mora, Gabriele

AU - Arosio, Alessandro

AU - Barberis, Marco

AU - Bartolomei, Ilaria

AU - Battistini, Stefania

AU - Benigni, Michele

AU - Borghero, Giuseppe

AU - Brunetti, Maura

AU - Calvo, Andrea

AU - Cammarosano, Stefania

AU - Cannas, Antonino

AU - Canosa, Antonio

AU - Capasso, Margherita

AU - Caponnetto, Claudia

AU - Caredda, Carla

AU - Carrera, Paola

AU - Casale, Federico

AU - Cavallaro, Sebastiano

AU - Chiò, Adriano

AU - Colletti, Tiziana

AU - Conforti, Francesca L.

AU - Conte, Amelia

AU - Corrado, Lucia

AU - Costantino, Emanuela

AU - D'Alfonso, Sandra

AU - Fasano, Antonio

AU - Femiano, Cinzia

AU - Ferrarese, Carlo

AU - Fini, Nicola

AU - Floris, Gianluca

AU - Fuda, Giuseppe

AU - Giannini, Fabio

AU - Mancardi, Gianluigi

AU - Mandich, Paola

AU - Messina, Sonia

AU - Mora, Gabriele

AU - Pisano, Fabrizio

AU - Ricci, Claudia

AU - Riva, Nilo

AU - Sabatelli, Mario

AU - Salvi, Fabrizio

AU - Sideri, Riccardo

AU - Spataro, Rossella

AU - Volanti, Paolo

AU - Zollino, Marcella

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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;00:1–12.

AB - 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;00:1–12.

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