Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
Department of Human Genetics, McGill University, Montréal, QC, Canada.
BMC Med. 2022 Nov 2;20(1):382. doi: 10.1186/s12916-022-02578-9.
Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR).
To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting. To do this, we extracted single nucleotide polymorphisms (SNPs) from the GWAS, which strongly associated with the 12 traits, and queried their effects in a large European ALS GWAS (27,265 cases and 110,881 controls). To avoid bias in our MR instruments related to the complex linkage disequilibrium structure of the human leukocyte antigen (HLA) region, we excluded SNPs within this region from the analyses. We computed inverse-variance weighted (IVW) MR estimates and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy. We also performed a reverse MR analysis testing the causal effects of ALS on the above autoimmune traits.
After applying Bonferroni correction for multiple testing, our MR analyses showed that the liability to autoimmune disorders does not affect ALS risk. Our reverse MR analysis also did not support the effects of liability to ALS on other autoimmune disorders. The results of the main IVW MR analyses were generally supported by our sensitivity MR analyses. The variance in the exposures explained by the sets of SNPs used as MR instruments ranged from 8.1 × 10 to 0.31. Our MR study was well-powered to detect effects as small as an odds ratio (OR) of 1.045 for ALS in the main MR and as small as an OR of 1.32 in the reverse MR.
Our MR study does not support a relationship between liability to autoimmune disorders and ALS risk in the European population. The associations observed in epidemiological studies could be partly attributed to shared biology or environmental confounders.
流行病学研究报告称，肌萎缩侧索硬化症（ALS）与不同的自身免疫性疾病之间存在关联。本研究旨在使用孟德尔随机化（MR）方法探索自身免疫性疾病与 ALS 之间的因果关系。
为了检验与免疫相关结局易感性相关的遗传预测效应对 ALS 风险的影响，我们在两样本 MR 框架中使用了最大的欧洲全基因组关联研究（GWAS）针对这些疾病的汇总统计数据。为此，我们从 GWAS 中提取与 12 种疾病强烈相关的单核苷酸多态性（SNP），并在大型欧洲 ALS GWAS 中查询其对 27265 例病例和 110881 例对照的影响。为避免与人类白细胞抗原（HLA）区域复杂的连锁不平衡结构相关的偏倚，我们从分析中排除了该区域内的 SNP。我们计算了逆方差加权（IVW）MR 估计值，并使用对水平多效性稳健的 MR 方法进行了敏感性分析。我们还进行了反向 MR 分析，以检验 ALS 对上述自身免疫性疾病的因果效应。
经过多重测试的 Bonferroni 校正后，我们的 MR 分析表明，自身免疫性疾病的易感性不会影响 ALS 风险。我们的反向 MR 分析也不支持 ALS 易感性对其他自身免疫性疾病的影响。主要 IVW MR 分析的结果普遍得到了我们的敏感性 MR 分析的支持。用作 MR 工具的 SNP 集合所解释的暴露方差范围为 8.1×10-8 至 0.31。我们的 MR 研究具有足够的效能来检测主要 MR 中 ALS 的 OR 为 1.045 和反向 MR 中 OR 为 1.32 这样小的效应。
我们的 MR 研究不支持欧洲人群中自身免疫性疾病易感性与 ALS 风险之间的关系。流行病学研究中观察到的关联可能部分归因于共同的生物学或环境混杂因素。
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