Polygenic associations and causal inferences between serum immunoglobulins and amyotrophic lateral sclerosis

Background: Due to the limitations like reverse causation and residual confounding commonly seen in the observational studies, the relationship between serum immunoglobulins and amyotrophic lateral sclerosis (ALS) remains unclear. Methods: Summary statistics from large-scale genome-wide association studies (GWAS) among European ancestry populations (similar to 15,000 individuals for serum immunoglobulins, and more than 36,000 individuals for ALS) were accessed and used in the discovery and replication phase, respectively. Polygenic risk score analysis was performed to test the polygenic association, and Mendelian randomization analysis was used to infer the causality. Results: An inverse polygenic association was discovered between IgA and ALS, as well as between IgM and ALS. Such associations were however not replicated using a larger GWAS of ALS, and no causal association was observed for either IgA-ALS or IgM-ALS. For IgG and ALS, a positive polygenic association was both discovered [odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.12-1.25, P = 5.9x10(-7)] and replicated (OR = 1.13, 95% CI: 1.06-1.20, P = 0.001). A causal association between IgG and ALS was suggested in the discovery analysis (OR = 1.06, 95 %CI: 1.02-1.10, P = 0.009), but it was not statistically significant in the replication analysis (OR = 1.07, 95 %CI: 0.90-1.24, P = 0.420). Conclusion: This study suggests a positive polygenic association between serum IgG and ALS.