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

Paria Alipour; Konstantin Senkevich; Jay P Ross; Dan Spiegelman; Despoina Manousaki; Patrick A Dion; Guy A Rouleau

doi:10.1186/s12916-022-02578-9

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

BMC Med. 2022 Nov 2;20(1):382. doi: 10.1186/s12916-022-02578-9.

Authors

Paria Alipour^{1

2}, Konstantin Senkevich^{1

3}, Jay P Ross^{1

2}, Dan Spiegelman^{1

3}, Despoina Manousaki^{4

5

6}, Patrick A Dion^{1

2}, Guy A Rouleau^{7

8

9}

Affiliations

¹ Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
² Department of Human Genetics, McGill University, Montréal, QC, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁴ Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, QC, Canada.
⁵ Department of Pediatrics, University of Montreal, Montréal, QC, Canada.
⁶ Research Center of the Sainte-Justine University Hospital, Montréal, QC, Canada.
⁷ Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada. guy.rouleau@mcgill.ca.
⁸ Department of Human Genetics, McGill University, Montréal, QC, Canada. guy.rouleau@mcgill.ca.
⁹ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada. guy.rouleau@mcgill.ca.

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.

Keywords: Amyotrophic lateral sclerosis; Autoimmune disorders; Causal relationship; Mendelian randomization.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis*
Autoimmune Diseases*
Genome-Wide Association Study / methods
Humans
Mendelian Randomization Analysis / methods
Polymorphism, Single Nucleotide

Grants and funding

U41 HG007823/HG/NHGRI NIH HHS/United States