Causal Effects of Red Cell Distribution Width on Rheumatoid Arthritis and Congestive Heart Failure: A Phenome-Wide Mendelian Randomization Study

Abstract Background Red cell distribution width (RDW) has been reported to be associated with many diseases, but there is no conclusive evidence to indicate a causal relationship between the two. This study aims to explore to determine the causal effects of high RDW on health with the help of phenome-wide association study (PheWAS), genome-wide association study (GWAS), and two-sample Mendelian randomization (MR). Results After multiple corrections, 235 of the 1,553 phenotypes were identified by PheWAS to be significantly associated with RDW. GWAS showed that RDW was associated with 27 independent single nucleotide polymorphisms, based on which the two-sample MR (the one sample for exposure, i.e., RDW from the PheWAS population and the other sample for disease outcomes from published GWAS summary data) confirmed that RDW had a statistically significant causal association with rheumatoid arthritis (OR,1.93; 95%CI:1.41–2.63) and congestive heart failure (OR,2.77; 95%CI:1.45–5.22). These results were robust to weak instrument bias, pleiotropy, and heterogeneity. Conclusions Our findings demonstrate that high RDW values may have a causal link with increased risk of rheumatoid arthritis and congestive heart failure, providing clues for further studies on the mechanisms for biologists and clinicians.