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.

中文翻译：

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血清免疫球蛋白与肌萎缩性侧索硬化之间的多基因关联和因果关系

慢性炎症可能会导致肌萎缩性侧索硬化症（ALS）的发展，但是血清免疫球蛋白与ALS风险之间的关系仍然不清楚。为了克服在观察性研究中常见的诸如反向因果关系和残留混杂的局限性，我们应用分子流行病学分析来检查血清免疫球蛋白与ALS之间的多基因和因果关系。来自不同血统的欧洲血统人群中的大规模全基因组关联研究（GWAS）的简要统计数据（血清免疫球蛋白约15000人，ALS超过36000人）。在发现阶段然后在复制阶段研究了三种类型的血清免疫球蛋白（IgA，IgM和IgG）与ALS之间的关系。使用PRSice软件包执行多基因风险评分（PRS）分析以测试多基因关联，并使用TwoSampleMR软件包执行孟德尔随机化（MR）分析以推断因果关系。在IgA和ALS之间以及IgM和ALS之间发现了反向多基因关联。但是，使用更大的GWAS ALS无法复制此类关联，并且对于IgA-ALS或IgM-ALS均未观察到因果关联。发现了正多基因关联[赔率（OR）= 1.18，95％置信区间（CI）：1.12-1.25，P = 5.9x10-7]，并且已复制（OR = 1.13，95％CI：1.06-1.20， P = 0.001）在IgG和ALS之间。发现（OR = 1.06，95％CI：1.02-1.10，P = 0.009）和复制（OR = 1.07，95％CI：0.90-1.24，P = 0.420）中也都建议IgG和ALS之间存在因果关系分析，尽管后者在统计上不显着。这项研究表明血清IgG（作为慢性炎症的生物标志物）和ALS之间存在共同的多基因风险。