Applying human genetics to interrogate the role of the human gut microbiome in cancer aetiology

Background Evidence from humans and model organisms supports relationships between the gut microbiome – a complex system of microorganisms aiding digestion, providing protection against pathogens and creating essential metabolites – and cancer aetiology.

However, human studies in this context have been largely observational and suffer confounding, biases and reverse causation, limiting their ability to offer convincing causal evidence.

The integration of human genetics within population health sciences has proved successful in facilitating improved causal inference (e.g., Mendelian randomization [MR]) and characterising inherited susceptibility for outcome risk assessment.

The former exploits properties of human genetic variation that approximate those of “instruments” to estimate the causal effect of a trait on health outcomes (i.e., the gut microbiome on cancer) and the latter uses aggregate genomic information to assess differential risk for lifecourse health outcomes.

Initial genome-wide association study (GWAS) results have enabled the application of MR to assess the impact of the microbiome on various outcomes; however, there is an unmet requirement for careful examination and interpretation of derived causal estimates and host (i.e., human) genetic effects.

Aims With the Cancer Research UK Population Research Postdoctoral Fellowship, I will interrogate the causal role of the human gut microbiome in cancer aetiology and the value added in this context by human genetics.

I will gather and appraise host microbiome-related genetic variation and apply contemporary causal inference methodologies to challenge the role of the gut microbiome in cancer aetiology (OB1), examine the likely effects of reverse causality in these relationships (OB2) and assess the association between genome-wide predictors of the gut microbiome and cancer risk outside causal framework analyses (OB3).

Methods Analyses will be performed using available GWAS summary-level data and individual-level data from cohort studies (the Flemish Gut Flora Project, Avon Longitudinal Study of Parents and Children, and UK Biobank).

Triangulating with evidence from epidemiological and basic sciences, I will use established and novel techniques to assess the validity of integrating human genetics in microbiome research, interrogating their appropriate implementation for appraising causality in cancer aetiology.

How the results will be used I will position the field by providing clarity on the role of the gut microbiome on cancers implicated in the literature but with little causal assessment. This will have implications for the evaluation and design of targeted strategies for cancer prevention.

Findings will provide an evaluation of the utility of human genetics with microbiome data, refining current applications in cancer research.