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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Amyotrophic Lateral Sclerosis | Research article

Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study

Authors: Paria Alipour, Konstantin Senkevich, Jay P. Ross, Dan Spiegelman, Despoina Manousaki, Patrick A. Dion, Guy A. Rouleau

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

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).

Methods

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.

Results

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 × 10−4 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.

Conclusion

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.
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Literature
1.
2.
3.
Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10(5-6):310–23.PubMedPubMedCentralCrossRef
4.
Gladman M, Zinman L. The economic impact of amyotrophic lateral sclerosis: a systematic review. Expert Rev Pharmacoecon Outcomes Res. 2015;15(3):439–50.PubMedCrossRef
5.
Cooper-Knock J, Jenkins T, Shaw PJ. editors. Clinical and molecular aspects of motor neuron disease. Colloq Ser Genomic Mol Med. 2013;2(2):1–60.CrossRef
6.
7.
Trabjerg BB, Garton FC, van Rheenen W, Fang F, Henderson RD, Mortensen PB, et al. ALS in Danish Registries: Heritability and links to psychiatric and cardiovascular disorders. Neurol Genet. 2020;6(2).
8.
Zhang R, Hadlock KG, Do H, Yu S, Honrada R, Champion S, et al. Gene expression profiling in peripheral blood mononuclear cells from patients with sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2011;230(1-2):114–23.PubMedCrossRef
9.
Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K, et al. Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2005;159(1-2):215–24.PubMedCrossRef
10.
Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci. 2017;20(2):136–44.PubMedCrossRef
11.
Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol. 2017;74(12):1446–54.PubMedPubMedCentralCrossRef
12.
13.
Kawamata T, Akiyama H, Yamada T, McGeer P. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Clin Pathol. 1992;140(3):691.
14.
Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004;55(2):221–35.PubMedCrossRef
15.
Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013;5(1):64–79.PubMedCrossRef
16.
Duarte F, Binet S, Lacomblez L, Bouche P, Preud’homme J-L, Meininger V. Quantitative analysis of monoclonal immunoglobulins in serum of patients with amyotrophic lateral sclerosis. J Neurol Sci. 1991;104(1):88–91.PubMedCrossRef
17.
Turner MR, Goldacre R, Ramagopalan S, Talbot K, Goldacre MJ. Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. Neurology. 2013;81(14):1222–5.PubMedPubMedCentralCrossRef
18.
Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methodol. 2017;26(5):2333–55.
19.
Davies NM, Holmes MV, Smith GD. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362.
20.
Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005–D12.PubMedCrossRef
21.
22.
23.
van Rheenen W, van der Spek R, Bakker M, van den Berg L, Veldink J, van Vugt J, et al. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021;53(12):1636–48.PubMedPubMedCentralCrossRef
24.
25.
Valette K, Li Z, Bon-Baret V, Chignon A, Bérubé J-C, Eslami A, et al. Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank. Commun Biol. 2021;4(1):1–15.CrossRef
26.
De Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017;49(2):256–61.PubMedPubMedCentralCrossRef
27.
Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. 2011;43(12):1193–201.PubMedPubMedCentralCrossRef
28.
Eijsbouts C, Zheng T, Kennedy NA, Bonfiglio F, Anderson CA, Moutsianas L, et al. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders. Nat Genet. 2021;53(11):1543–52.PubMedPubMedCentralCrossRef
29.
Consortium IMSG, ANZgene, IIBDGC, WTCCC2. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365(6460):eaav7188.CrossRef
30.
Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, et al. An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs. J Hepatol. 2021;75(3):572–81.PubMedPubMedCentralCrossRef
31.
Ji S-G, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017;49(2):269–73.PubMedCrossRef
32.
Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44(12):1341–8.PubMedPubMedCentralCrossRef
33.
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376–81.PubMedCrossRef
34.
Forgetta V, Manousaki D, Istomine R, Ross S, Tessier M-C, Marchand L, et al. Rare genetic variants of large effect influence risk of type 1 diabetes. Diabetes. 2020;69(4):784–95.PubMedPubMedCentralCrossRef
35.
Bentham J, Morris DL, Graham DSC, Pinder CL, Tombleson P, Behrens TW, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–64.PubMedPubMedCentralCrossRef
36.
Hemani G, Tilling K, Davey SG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017;13(11):e1007081.PubMedPubMedCentralCrossRef
37.
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408.PubMedPubMedCentralCrossRef
38.
Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 2017;18(1):1–21.CrossRef
39.
Burgess S, Thompson SG, Collaboration CCG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.PubMedCrossRef
40.
Burgess S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome. Int J Epidemiol. 2014;43(3):922–9.PubMedPubMedCentralCrossRef
41.
42.
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25.PubMedPubMedCentralCrossRef
43.
Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65.PubMedPubMedCentralCrossRef
44.
Burgess S, Bowden J, Fall T, Ingelsson E, Thompson SG. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology. 2017;28(1):30.PubMedCrossRef
45.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14.PubMedPubMedCentralCrossRef
46.
Bowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728–42.PubMedCrossRef
47.
Verbanck M, Chen C-y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef
48.
McGovern DP, Gardet A, Törkvist L, Goyette P, Essers J, Taylor KD, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010;42(4):332–7.PubMedPubMedCentralCrossRef
49.
Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol. 2015;181(4):251–60.PubMedPubMedCentralCrossRef
50.
Burgess S, Smith GD, Davies NM, Dudbridge F, Gill D, Glymour MM, et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 2019;4.
51.
Bowden J, Hemani G, Davey SG. Invited commentary: detecting individual and global horizontal pleiotropy in Mendelian randomization—a job for the humble heterogeneity statistic? Am J Epidemiol. 2018;187(12):2681–5.PubMedPubMedCentral
52.
Li CY, Yang TM, Ou RW, Wei QQ, Shang HF. Genome-wide genetic links between amyotrophic lateral sclerosis and autoimmune diseases. BMC Med. 2021;19(1):1–11.CrossRef
Metadata
Title
Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study
Authors
Paria Alipour
Konstantin Senkevich
Jay P. Ross
Dan Spiegelman
Despoina Manousaki
Patrick A. Dion
Guy A. Rouleau
Publication date
01-12-2022

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