Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis

Abstract

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood pathophysiology. Recent studies have highlighted systemic inflammation, especially the role of circulating inflammatory proteins, in ALS.

Methods: This study investigates the potential causal link between these proteins and ALS. We employed a two-sample Mendelian Randomization(MR) approach, analyzing data from large-scale genome-wide association studies to explore the relationship between 91 circulating inflammatory proteins and ALS. This included various MR methods like MR Egger, weighted median, and inverse-variance weighted, complemented by sensitivity analyses for robust results.

Results: Significant associations were observed between levels of inflammatory proteins, including Adenosine Deaminase, Interleukin-17C, Oncostatin-M, Leukemia Inhibitory Factor Receptor, and Osteoprotegerin, and ALS risk. Consistencies were noted across different P-value thresholds. Bidirectional MR suggested that ALS risk might influence levels of certain inflammatory proteins.

Discussion: Our findings, via MR analysis, indicate a potential causal relationship between circulating inflammatory proteins and ALS. This sheds new light on ALS pathophysiology and suggests possible therapeutic targets. Further research is required to confirm these results and understand the specific roles of these proteins in ALS.

Keywords: amyotrophic lateral sclerosis; circulating inflammatory protein; osteoprotegerin; tumor necrosis factor; two-sample mendelian randomization.

Figure 1

Flowchart figure.

Figure 2

Adopt a significance threshold for selecting SNPs of p < 5 × 10⁻⁸. In this Mendelian randomization analysis, inflammatory proteins are analyzed as the exposure factor, with ALS as the resultant outcome. Significant findings are denoted by a P_IVW value less than 0.05.

Figure 3

Adopt a significance threshold for selecting SNPs of p < 5 × 10⁻⁷. In this Mendelian randomization analysis, inflammatory proteins are analyzed as the exposure factor, with ALS as the resultant outcome. Significant findings are denoted by a P_IVW value less than 0.05.

Figure 4

Adopt a significance threshold for selecting SNPs of p < 5 × 10⁻⁶. In this Mendelian randomization analysis, inflammatory proteins are analyzed as the exposure factor, with ALS as the resultant outcome. Significant findings are denoted by a P_IVW value less than 0.05.

Figure 5

Displays the leave-one-out analysis results using the IVW method, assessing the impact of individual SNPs on the overall MR findings by sequentially excluding each SNP. The Y-axis corresponds to each excluded rsID and the aggregate IVW method result without any SNP exclusions. The X-axis represents the specific IVW values, where black and red dots denote beta effect values, and the lines indicate the confidence intervals of the beta values. Specifically, (A,B) illustrate the leukemia inhibitory factor receptor levels as the exposure, with SNP thresholds set at p < 5 × 10⁻⁸ and p < 5 × 10⁻⁷, respectively. (C,D) focus on osteoprotegerin levels as the exposure, applying SNP thresholds of p < 5 × 10⁻⁷ and p < 5 × 10⁻⁶. Finally, the levels of adenosine deaminase as the exposure factor are examined in (E–G), with SNP thresholds set at p < 5 × 10⁻⁸, p < 5 × 10⁻⁷, and p < 5 × 10⁻⁶, respectively.

Figure 6

MR Results with Adenosine Deaminase Correction. SNP selection thresholds are applied with p-values <5 × 10⁻⁸, p < 5 × 10⁻⁷, and p < 5 × 10⁻⁶, respectively. Adenosine Deaminase protein is considered as the exposure factor, and ALS as the outcome in the Mendelian randomization analysis.

Figure 7

Reverse MR Results. Mendelian randomization analysis with ALS as the exposure factor and inflammatory proteins as the outcome, considering significance with p_ivw < 0.05.

Figure 8

Leave-One-Out Analysis Results for Various Outcomes with ALS Exposure. This series illustrates the influence of ALS as an exposure factor on different inflammatory markers, using the leave-one-out methodology to assess the impact of individual SNPs on the overall results. (A): C-C motif chemokine 20 levels as the outcome, with ALS as the exposure; (B): Interleukin-5 levels as the outcome, with ALS as the exposure; (C): Tumor necrosis factor ligand superfamily member 12 levels as the outcome, with ALS as the exposure.

Figure 9

Significant Mendelian Randomization Results of Inflammatory Proteins with ALS Validation Sets (p_ivw < 0.05 denotes significance). “Sporadic” denotes a cohort of sporadic ALS, while “Mixed” refers to a combined cohort of familial and sporadic ALS.