Chronic inflammation might contribute to the development of amyotrophic lateral sclerosis (ALS), the relationship between serum immunoglobulins and risk of ALS remains however unclear. In order to overcome limitations like reverse causation and residual confounding commonly seen in the observational studies, we applied molecular epidemiological analyses to examine the polygenic and causal associations between serum immunoglobulins and ALS. Summary statistics from the large-scale genome-wide association studies (GWAS) among European ancestry populations ([~]15000 individuals for serum immunoglobulins, and more than 36000 individuals for ALS) were accessed from different consortia. The relationships between three types of serum immunoglobulins (IgA, IgM, and IgG) and ALS were investigated in a discovery phase and then in a replication phase. Polygenic risk score (PRS) analysis was performed with PRSice package to test the polygenic association, and Mendelian randomization (MR) analysis was performed with TwoSampleMR package to infer the causality. 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. 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) between IgG and ALS. A causal association between IgG and ALS was also suggested in both the discovery (OR=1.06, 95%CI: 1.02-1.10, P=0.009) and replication (OR=1.07, 95%CI: 0.90-1.24, P=0.420) analyses, although the latter was not statistically significant. This study suggests a shared polygenic risk between serum IgG (as a biomarker for chronic inflammation) and ALS.
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