In this two-sample MR analysis, we leveraged the largest genetic data set for educational attainment published to date, together with the largest GWAS addressing the outcome of interest, to understand causal relationships between educational attainment and risk of RA. We identified a pronounced causal effect that genetic predisposition to higher educational attainment was associated with a lower risk of RA.
In fact, education inequalities in risk of RA have long been noted. Pincus and colleagues [26] identified an association between a lower level of formal education and higher mortality and morbidity related to RA over a 9-year period. Another study found that formal education level can be a significant marker of clinical status in RA [27]. However, some studies have revealed that level of formal education is not significantly associated with risk of RA [28, 29].
Given that these studies with inconsistent conclusions were either based on limited samples or only explored correlations from epidemiological observational studies, few studies have clearly and consistently demonstrated a biological link underlying this association. By applying MR analysis in the current study to alleviate these problems, we provided concrete evidence to support an inverse causal association of educational attainment with risk of RA. The credibility of this study was verified by using several data sets with largest sample size.
A previous two-sample MR study conducted by Bae and Lee [30] suggested that RA risk decreased by 52% per SD (approximately 3.61 years) increased in the years of schooling completed used relatively small sample size statistical data set of years of education from the UK Biobank GWAS (n = 293,723) as the exposure and a meta-analysis of GWAS of RA (n = 5539) and European controls (n = 20,169) as the outcome. Here, we expanded the exposure sample size to over 1 million individuals (N = 1,131,881) and chose the latest meta-analysis of GWAS, which included 58,284 individuals of European ancestry (14,361 RA cases and 43,923 controls). Meanwhile, the number of SNPs chosen as instrumental variables increased dramatically (from 49 to 373). Furthermore, individuals with RA who were seropositive and seronegative for ACPA or RF were enrolled in this MR analysis. Recently, a comparable analysis has been carried out by Yuan et al. used the same GWAS as sources for educational attainment (EA, exposure) and rheumatic arthritis (RA, outcome) [31]. And they found that RA risk decreased by 50% per SD (approximately 4.2 years) increased in the years of schooling completed. However, there are some differences that should be noticeable between our study and the Yuan’s. Firstly, the linkage disequilibrium (LD) r2 of the SNPs in our study was set to a more conservative threshold to obtain a smaller set of SNPs (LD r2 < 0.001 with 387 SNPs remained vs. LD r2 < 0.01 with 663 SNPs used in Yuan’s study) to ensure the independence of SNPs at the cost of decreasing statistical power. Secondly, the RA phenotype used in Yuan’s study came from mixed populations (European and Asian ancestry). However, it should be noticed that population heterogeneity may lead to bias to the MR results. As such, all the association analyses performed in our study were restricted to European-descent individuals, making the MR estimates more reliable. As such, our MR study is based on merely European descents and a set of more conservative genetic instruments, to appraise the causal relationship between EA and the risk of RA. Thus, the causative association fully explored in patients between educational attainment and risk of RA was more convincing.
In total, the identified exposure SNPs accounted for approximately 11% of the variance in educational attainment. The effect size of the independent SNPs corresponding to an educational increase was obtained as follows: the median effect size corresponded to 1.7 weeks of schooling per allele (95% CI: 1.1–2.6 weeks). Furthermore, the genes related to these SNPs are involved in almost all aspects of neuron-to-neuron communication [17]. The dramatic increase in our sample size enabled us to improve the power of the test.
The MR approach, as an approximation to a randomized controlled trial in nature, offers one of the most compelling methods to detect causation. The IVW method and weighted median method suggested an inverse causal association between educational attainment and RA, whereas the MR-Egger method showed no proof of a causative association between educational attainment and RA. However, the MR-Egger test provided a reference for the direction of causal association. The weighted median method, which is not influenced by outlying genetic variants, improved the power of causal effect detection and effectively decreased type I error [19]. Therefore, the weighted median method had a distinct advantage over the MR-Egger test, and its result in this study was the same as that of the IVW method.
The results of our MR analysis might be biased by pleiotropy. Heterogeneity tests suggested an apparent sign of heterogeneity (Q value (df) = 594.21(372), p = 1.82 × 10− 12). However, heterogeneity was decreased after removing the outlying SNP detected by MR PRESSO test (Q value (df) = 425.7(371), p = 0.03). Additionally, there was no indication of unbalanced pleiotropy (p-value for MR Egger intercept = 0.34). Therefore, we deemed that the conclusion would not be biased significantly by the heterogeneity of the analysis because several robust methods were performed, which could provide reliable inferences and statistical support.
The potential mechanisms that educational attainment ultimately reduces the risk of RA may be complicated. In general, higher educational attainment is associated with greater wealth and status, as well as healthier lifestyle and relatively higher quality of life. This cascade of benefits from higher educational attainment may eventually contribute to RA prevention. In addition, the effect of educational attainment on RA may also be mediated by obesity. In an MR study, Böckerman et al. found that the higher years of schooling was associated with lower BMI [32]. Another MR study has also shown that higher years of schooling was associated with lower plasma triglyceride levels, waist circumference and waist-to-hip ratio [33]. This study suggests that higher education attainment can protect against obesity to some extent and higher educational attainment could be a protective factor against obesity in advanced countries [32]. What’s more, previous study has shown that lower educational attainment was associated with an increased risk of Type 2 Diabetes Mellitus (T2DM) [33]. And T2DM was a significant risk factor for RA [25, 34]. And Qian et al. has found that genetic predisposition to smoking was positively associated with rheumatoid arthritis [23]. To some extent, some studies have found that well-educated individuals were less likely to smoke [35,36,37]. Based on the points discussed above, the influence of educational attainment on individuals has multiple aspects, and the total vector effects reflected in RA is the preventive effect. However, the potential biological mechanisms were rarely reported. Further researches are needed to uncover the pathways about how the educational attainment decreases the risk of RA.
This study has several limitations. The summary GWAS data were restricted to individuals of European descent, and, because ethnicity may affect causality, our results may not be fully representative of the non-European populations. Another limiting factor was that this applied analysis could not be stratified by gender and age due to the meta-GWAS was performed without adjustment for gender or age to maximize statistical power, thus, we could not assess gender or age discrepancies and potential nonlinear associations.
In conclusion, our aim in this study was to assess the causal effect of educational attainment and risk of RA by using two-sample MR analysis with pretty large sample sizes. However, further confirmatory methods should be conducted to verify our findings of a potential causal association between increased educational attainment and lower risk of RA. These results advocate the current clinical practice for RA surveillance in those with lower educational attainment.