Peripheral immunity has been observed to be associated with amyotrophic lateral sclerosis (ALS) clinically, but whether there exist causal association and the effect direction is controversial and elusive. The objective of this study is to explore the causal relationship of peripheral immune cell traits including total leukocytes count, monocyte count, neutrophil count, eosinophil count, basophil count, and lymphocyte count on ALS risk. We conducted a two-sample Mendelian randomization analysis to estimate the causal effects. Significant single nucleotide polymorphisms from genome-wide association study on human blood cell traits were utilized as exposure instruments and summary statistics of ALS as outcome. The causal relationship was evaluated by inverse variance weighted, MR Egger regression and weighted median methods, and further verified by extensive sensitivity analyses. We found that genetically determined one standard deviation increase in total leukocytes count was associated with lower risk of ALS (OR: 0.906, 95% CI: 0.842–0.974, P: 0.007) after Bonferroni correction, and increased neutrophil count showed suggestive association with reduced ALS risk (OR: 0.926, 95% CI: 0.858–1.000, P: 0.049). The results were robust under all sensitivity analyses. Our study reveals a genetic predisposition to higher peripheral leukocytes with an inverse causal effect on the risk of ALS, highlighting the important role of peripheral immunity in the development of ALS.

临床上已观察到外周免疫与肌萎缩性侧索硬化症（ALS）有关，但是否存在因果关联且其作用方向尚有争议且难以捉摸。这项研究的目的是探讨外周免疫细胞性状（包括总白细胞计数，单核细胞计数，中性粒细胞计数，嗜酸性粒细胞计数，嗜碱性粒细胞计数和淋巴细胞计数）与ALS风险的因果关系。我们进行了两次样本孟德尔随机分析，以评估因果关系。来自全基因组范围的人类血细胞性状关联研究的重要单核苷酸多态性被用作暴露手段，并以ALS的摘要统计作为结果。通过反方差加权，MR Egger回归和加权中位数方法评估因果关系，并通过广泛的敏感性分析进一步验证。我们发现，从遗传角度确定，白细胞总数增加一个标准差与ALS风险降低相关（OR：0.906、95％CI：0.842–0.974，Bonferroni校正后，P：0.007），中性粒细胞计数增加提示ALS风险降低（OR：0.926，95％CI：0.858–1.000，P：0.049）。在所有敏感性分析下，结果都是可靠的。我们的研究揭示了较高的外周白细胞的遗传易感性，对ALS的危险具有负因果关系，突出了外周免疫在ALS发生中的重要作用。