Causal Association of Leukocytes Count and Amyotrophic Lateral Sclerosis: a Mendelian Randomization Study
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ORIGINAL ARTICLE
Causal Association of Leukocytes Count and Amyotrophic Lateral Sclerosis: a Mendelian Randomization Study Chunyu Li 1 & Wanchun Yang 2 & Qianqian Wei 1 & Huifang Shang 1 Received: 1 June 2020 / Accepted: 30 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Amyotrophic lateral sclerosis . Leukocytes count . Mendelian randomization . Causality
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the death of lower and upper motor neurons leading to paralysis of muscles [1]. Although several pathological mechanisms underlying ALS have been proposed, the etiology of ALS remains unclear. Current research evidence implicates that dysregulated immunity is associated with ALS [2]. Chunyu Li and Wanchun Yang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02053-7) contains supplementary material, which is available to authorized users. * Huifang Shang [email protected] 1
Department of Neurology, Laboratory of Neurodegenerative Disorders, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu 610041, Sichuan, China
2
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China
A prominent pathological feature of ALS is the neuroinflammation within the central nervous system (CNS) [3], as well as perivascular infiltration of monocytes and T cells [4]. Although ALS is considered as a disease with dysregulated immu
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