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

Abstract BackgroundWhy 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. MethodsWe 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. ResultsOur 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. ConclusionsOur 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. Key messagesThe risk of infectious disease acquisition is dependent on many interacting sociodemographic, lifestyle, clinical, genetic, environmental, and national and international health governance factors.Traditional epidemiological studies of these risk factors are often hindered by issues of confounding and therefore whether a given putative risk factor is causally associated with infection acquisition is difficult to decipher.Using Epstein Barr Virus (EBV) as a model pathogen, we demonstrate the power of Mendelian randomization to understand if putative risk factors are causal, while controlling for confounding.Better understanding of infectious disease risk factors using Mendelian randomization can inform vaccine strategies and deployment e.g. by identifying priority populations for vaccination.