Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Area of Science:

• Genetics
• Neuroscience
• Epidemiology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complex etiology.
• Understanding shared genetic risk factors and causal relationships is crucial for identifying potential therapeutic targets and preventative strategies for ALS.

Purpose of the Study:

• To identify shared polygenic risk factors between amyotrophic lateral sclerosis (ALS) and a wide range of phenotypic traits.
• To investigate potential causal relationships between various traits and ALS using Mendelian randomization.
• To develop a public resource for the ALS research community.

Main Methods:

• Utilized linkage disequilibrium (LD) score regression to assess genetic correlations between ALS and over 700 traits.
• Employed Mendelian randomization (MR) analysis to infer causal relationships, using publicly available genome-wide association studies (GWAS) summary statistics.
• Performed multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses.

Main Results:

• Identified significant polygenic risk sharing between ALS and traits including smoking status, physical activity levels, cognitive performance, and educational attainment.
• Found evidence suggesting hyperlipidemia, specifically elevated low-density lipoprotein cholesterol, as a causal risk factor for ALS.
• Localized putative functional genetic signals within relevant loci.

Conclusions:

• Shared polygenic risk exists between ALS and several lifestyle and cognitive traits.
• Elevated low-density lipoprotein cholesterol is identified as a potential causal risk factor for ALS.
• A publicly accessible resource was developed to aid the ALS research community, with plans for future expansion.