Unpicking the Gordian knot: Mendelian randomization to elucidate the risk factors for infectious diseases, using EBV as a model pathogen

Abstract

Background Why particular individuals are more at risk of a given infectious disease than others has been a topic of interest for scientists, clinicians, and polymaths for millennia. Complex webs of factors- sociodemographic, clinical, genetic, environmental- intersect, rendering causality difficult to decipher. We aimed to demonstrate the ability of Mendelian Randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of infectious diseases, using Epstein Barr Virus (EBV) as a model pathogen. Methods We mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8,422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal. Results Our GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed educational attainment, number of sexual partners, and smoking as causal risk factors for EBV serostatus. Conclusions Our study demonstrates the power of MR to decipher complex webs of putative risk factors and determine which are causal for the acquisition of an infectious disease. The factors identified for EBV will be important for vaccine deployment.