Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis.

Sara Bandres‐Ciga,Gabriele Mora,Mike A Nalls,Pentti J Tienari,Andrea Calvo,The Italsgen Consortium ,David J Stone,Alastair J Noyce,The International Als Genomics Consortium ,Aude Nicolas,Bryan J Traynor,Andrew B Singleton,Adriano Chiò,Gibran Hemani

doi:10.1002/ana.25431

Abstract

ObjectiveTo identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS).MethodsLinkage 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.ResultsWe 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.InterpretationHere, 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

Highlights

Traits Genetically Correlated to amyotrophic lateral sclerosis (ALS) by linkage disequilibrium (LD) Score Regression Our analyses identified 18 traits that were genetically correlated to ALS after adjusting for multiple testing by false discovery rate (Table 1)
Traits Causally Linked to ALS by Mendelian Randomization We identified the phenotypic traits LDL cholesterol and coronary heart disease in the published genome-wide association studies (GWASes), and selfreported high cholesterol in the UK Biobank, as being causally linked to ALS risk
We used these results from nearly 25 million individuals (24,538,000 from published Genome-wide association studies (GWAS) and $337,159 from UKBB studies) to establish a public resource that can be accessed by other researchers to explore risk factors and shared disease mechanisms in ALS

Summary

Objective

To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Genome-wide association studies (GWAS) have revolutionized human genetics and have led to the discovery of thousands of risk variants involved in disease etiology.[6] From the perspective of ALS research, summary statistics from hundreds of these studies have been published online in an effort to facilitate the application of current generation genomic techniques, such as linkage disequilibrium (LD) score regression testing and Mendelian randomization. Both methodologies are powerful tools to assess causality and investigate the extent to which genetic etiologies are shared across different diseases. We created an online resource (https://lng-nia.shinyapps.io/ mrshiny) that can be used by the ALS community to inform pleiotropy or causality when undertaking observational studies or pursuing disease-modifying interventions

Materials and Methods

Results

Discussion