J Rheum Dis.  2022 Jan;29(1):46-51. 10.4078/jrd.2022.29.1.46.

Mendelian Randomization Research on the Relationship Between Rheumatoid Arthritis and Systemic Lupus Erythematosus and the Risk of Autistic Spectrum Disorder

Affiliations
  • 1Department of Rheumatology, Korea University College of Medicine, Seoul, Korea

Abstract


Objective
The purpose of this study was to examine whether there is a causal link between rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and autism spectrum disorder (ASD).
Methods
We used inverse variance weighted (IVW), weighted median, and MR-Egger regression methods to perform two-sample Mendelian randomization (MR) study using publicly available summary statistics datasets. In addition, we employed genome-wide association studies (GWASs) for RA and SLE as exposure and an ASD GWAS as an outcome.
Results
Thirty-three and 28 single-nucleotide polymorphisms from RA and SLE GWASs were selected as instrumental variables for ASD. The IVW method revealed no evidence supporting a causal association between RA and SLE and risk for ASD (beta=−0.077, standard error [SE]=0.041, p=0.062; beta=0.014, SE=0.021, p=0.493). The weighted median approach yielded no evidence of any causal association between RA and SLE and risk for ASD (beta=−0.071, SE=0.058, p=0.223; beta=0.045, SE=0.030, p=0.130). MR-Egger analysis demonstrated no causal association between RA and SLE and risk for ASD (beta=−0.062, SE=0.079, p=0.434; beta=0.048, SE=0.043, p=0.273). The MR results calculated using IVW, the median weighted and the MR-Egger regression approaches were consistent.
Conclusion
The findings of the MR analysis did not support a causal relationship between RA or SLE and the risk of ASD.

Keyword

Rheumatoid arthritis; Systemic lupus erythematosus; Autism; Mendelian randomization analysis

Figure

  • Figure 1 Forest plot of the causal effects of rheumatoid arthritis- (A) and systemic lupus erythematosus- (B) associated single-nucleotide polymorphisms on the risk for autism spectrum disorder (ASD). IVW: inverse variance weighted, MR: Mendelian randomization.

  • Figure 2 Scatterplots of genetic associations with rheumatoid arthritis (A) and systemic lupus erythematosus (B) versus genetic associations with autism spectrum disorder. The slopes of each line represent causal associations for each method. The blue, green, and dark lines represent the inverse variance-weighted, weighted median, and mendelian randomization‐Egger estimates, respectively. SNP: single-nucleotide polymorphism.

  • Figure 3 Funnel plot assessing heterogeneity.


Reference

1. Lai MC, Lombardo MV, Baron-Cohen S. 2014; Autism. Lancet. 383:896–910. DOI: 10.1016/S0140-6736(13)61539-1.
2. Rom AL, Wu CS, Olsen J, Jawaheer D, Hetland ML, Mørch LS. 2018; Parental rheumatoid arthritis and autism spectrum disorders in offspring: a Danish nationwide cohort study. J Am Acad Child Adolesc Psychiatry. 57:28–32.e1. DOI: 10.1016/j.jaac.2017.10.002. PMID: 29301665.
3. Keil A, Daniels JL, Forssen U, Hultman C, Cnattingius S, Söderberg KC, et al. 2010; Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology. 21:805–8. DOI: 10.1097/EDE.0b013e3181f26e3f. PMID: 20798635. PMCID: PMC3115699.
4. Wojcik S, Bernatsky S, Platt RW, Pineau CA, Clarke AE, Fombonne É, et al. 2017; Risk of autism spectrum disorders in children born to mothers with rheumatoid arthritis: a systematic literature review. Arthritis Care Res (Hoboken). 69:1926–31. DOI: 10.1002/acr.23235. PMID: 28319657.
5. Tsai PH, Yu KH, Chou IJ, Luo SF, Tseng WY, Huang LH, et al. 2018; Risk of autism spectrum disorder in children born to mothers with systemic lupus erythematosus and rheumatoid arthritis in Taiwan. Joint Bone Spine. 85:599–603. DOI: 10.1016/j.jbspin.2017.11.005. PMID: 29183859.
6. Zhu Z, Tang S, Deng X, Wang Y. 2020; Maternal systemic lupus erythematosus, rheumatoid arthritis, and risk for autism spectrum disorders in offspring: a meta-analysis. J Autism Dev Disord. 50:2852–9. DOI: 10.1007/s10803-020-04400-y. PMID: 32034648.
7. Hill HA, Kleinbaum DG. Armitage P, Colton T, editors. 2000. Bias in observational studies. Encyclopedia of biostatistics. Chichester, John Wiley & Sons.
8. Burgess S, Daniel RM, Butterworth AS, Thompson SG. 2015; Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol. 44:484–95. DOI: 10.1093/ije/dyu176. PMID: 25150977. PMCID: PMC4469795.
9. Lee YH, Song GG. 2019; Causal association between rheumatoid arthritis with the increased risk of type 2 diabetes: a Mendelian randomization analysis. J Rheum Dis. 6:131–6. DOI: 10.4078/jrd.2019.26.2.131.
10. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. 2014; Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 506:376–81. DOI: 10.1038/nature12873. PMID: 24390342. PMCID: PMC3944098.
11. Bentham J, Morris DL, Graham DSC, Pinder CL, Tombleson P, Behrens TW, et al. 2015; Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 47:1457–64. DOI: 10.1038/ng.3434. PMID: 26502338. PMCID: PMC4668589.
12. Cross-Disorder Group of the Psychiatric Genomics Consortium. 2013; Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 381:1371–9. DOI: 10.1016/S0140-6736(12)62129-1.
13. Hartwig FP, Davies NM, Hemani G, Davey Smith G. 2016; Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int J Epidemiol. 45:1717–26. DOI: 10.1093/ije/dyx028. PMID: 28338968. PMCID: PMC5722032.
14. Pierce BL, Burgess S. 2013; Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 178:1177–84. DOI: 10.1093/aje/kwt084. PMID: 23863760. PMCID: PMC3783091.
15. Bowden J, Davey Smith G, Burgess S. 2015; Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 44:512–25. DOI: 10.1093/ije/dyv080. PMID: 26050253. PMCID: PMC4469799.
16. Bowden J, Davey Smith G, Haycock PC, Burgess S. 2016; Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 40:304–14. DOI: 10.1002/gepi.21965. PMID: 27061298. PMCID: PMC4849733.
17. Hemani G, Zheng J, Wade KH, Laurin C, Elsworth B, Burgess S, et al. 2018. MR-Base: a platform for systematic causal inference across the phenome using billions of genetic associations. BioRxiv. 078972 [Preprint]. https://doi.org/10.1101/78972. cited 2018 May 30.
18. Egger M, Smith GD, Phillips AN. 1997; Meta-analysis: principles and procedures. BMJ. 315:1533–7. DOI: 10.1136/bmj.315.7121.1533. PMID: 9432252. PMCID: PMC2127925.
19. Chen SW, Zhong XS, Jiang LN, Zheng XY, Xiong YQ, Ma SJ, et al. 2016; Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav Brain Res. 296:61–9. DOI: 10.1016/j.bbr.2015.08.035. PMID: 26327239.
20. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. 2007; Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 27:10695–702. DOI: 10.1523/JNEUROSCI.2178-07.2007. PMID: 17913903. PMCID: PMC2387067.
21. Gata-Garcia A, Diamond B. 2019; Maternal antibody and ASD: clinical data and animal models. Front Immunol. 10:1129. DOI: 10.3389/fimmu.2019.01129. PMID: 31191521. PMCID: PMC6547809.
22. Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA, et al. 2009; HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med. 163:542–6. DOI: 10.1001/archpediatrics.2009.74. PMID: 19487610.
23. Swerdlow DI, Kuchenbaecker KB, Shah S, Sofat R, Holmes MV, White J, et al. 2016; Selecting instruments for Mendelian randomization in the wake of genome-wide association studies. Int J Epidemiol. 45:1600–16. DOI: 10.1093/ije/dyw088. PMID: 27342221. PMCID: PMC5100611.
Full Text Links
  • JRD
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr