In this study, the effects of IVs on the exposure (i.e., PBC) and outcome (i.e., RA) from two independent samples were used in a two-sample MR analysis. Based on summary-level data, we employed a series of statistical methods to obtain quantitative estimates of the impact of PBC on RA. Reverse MR analysis was used to examine the causality between RA and PBC. To our knowledge, this study is the first to use MR analysis and large-scale GWAS datasets to demonstrate a causal relationship between PBC and RA. Our study found that PBC has a positive causal effect on RA risk; however, RA has no causal effect on PBC risk in Europeans. We discovered that PBC could increase the likelihood of developing RA, implying that PBC and RA may have a similar pathophysiology.
Understanding the etiology of disease processes requires inferring causal links between phenotypes, which is a major challenge. Owing to two significant achievements in the past decade, the possibility of phenome-wide causal inference has increased dramatically. The first is the persistent success of GWAS in discovering strong genetic correlations . The second is the development of statistical methods for causal inference that rely on MR principles and GWAS summary data .
While numerous studies have found that approximately 1.8–5.6% of patients with PBC have RA  and that patients with RA are at a higher risk of developing PBC than the general population , these findings do not prove whether PBC is etiologically related to RA. Based on the GWAS summary data and two-sample MR analysis, our results indicate that the presence of PBC with RA may be due to a causal link rather than an observation.
Our study has several advantages over prior observational studies. First, we analyzed large-scale GWAS datasets, and over 500,000 people participated in the RA GWAS alone. The participants in both studies were of European ancestry, thus minimizing any population stratification. Second, because the SNP site alleles are randomly assigned in advance of the commencement of any potential confounding circumstances, MR substantially reduces the influence of confounding factors and reverse causation [13, 20]. Finally, we validated the robustness of the results using various MR methodologies. An unbiased causal estimate could still be obtained when some instruments were missing or when there was horizontal pleiotropy.
However, our study had certain limitations. First, using summary-level statistics prevented us from performing analyses stratified by factors that were altered in the original GWAS . Second, in the MR model, we only assumed a linear relationship between PBC and RA. We were also unable to investigate the nonlinearity of the relationship between PBC and RA using summary statistics. Third, we did not stratify the causative effects of PBC and RA by sex or age, despite previous research showing that they can vary by these factors [2, 28]. Individual-level data from the original GWAS were difficult to acquire. The European ancestry of the GWAS population included in the exposure and outcome analyses may have mitigated population stratification. Fourth, the minimal variance in exposures, particularly for RA using SNP instruments, may reduce the strength of the causal effects. A modest number of SNP instruments may have an impact on variance. Nevertheless, owing to the very large sample size and highly relevant instruments, we were still able to establish or exclude causal associations.
In addition to earlier evidence from genetic, immunological, and environmental levels, a causal effect of PBC on RA has been shown; therefore, it is important for the clinician to consider the association of PBC and RA in daily practice. Awareness of this combination should encourage clinicians to screen for PBC with AMAs testing in patients with abnormal liver tests, as well as to recognize that abnormal liver tests in RA patients are not always associated with drugs. Furthermore, if the pharmacological target is discovered in the pathogenesis of the two diseases, optimized management of one might possibly benefit the other. Novel effective medications (e.g., infliximab, rituximab, abatacept, and tocilizumab) hold considerable promise for the treatment of both PBC and RA [29–32]. Several have received preliminary approval, thereby increasing the likelihood that they will be identified and confirmed as beneficial.