On the use of genetic information in causal inference for human complex diseases: a collection of studies on cancers

Abstract

The introduction chapter (Chapter 1) starts with a summary of recent progress in genetic epidemiology. The advancement of genotyping technology made it feasible to revisit a 30 years old study design known as Mendelian randomization (MR) where germline genetic variants can be used as natural instruments to assess causality between human complex traits. Here the rationale and technical assumptions required to conduct feasible MR studies were explained. The overall thesis objective and study approaches used in the thesis were also outlined. The final subchapter provides details on the definition of disease phenotypes that will be used throughout the thesis, including the creation of a "pan-cancer" phenotype, a combined cancer outcome of whether a person is diagnosed with any cancer, which was subsequently used in Chapter 4 and 5.In Chapters 2 and 3, I investigated whether MR can be used to infer causality between modifiable risk factors and specific cancers. For Chapter 2, I applied MR to evaluate the link between vitamin D and coffee intake on epithelial ovarian carcinomas (EOC). This was done in a two-sample MR framework where genetic instruments for the risk factor were obtained from public GWAS literature and the cancer GWAS statistics were obtained from the Ovarian Cancer Association Consortium (OCAC). While higher genetically predicted vitamin D reduced the risk of EOC, there was no evidence to support a link between genetically predicted coffee intake and EOC. For Chapter 3, I contrasted and compared the association between alcohol intake with breast and ovarian cancer using both MR and observational analyses. Genetic summary statistics were obtained from the OCAC and BCAC (breast cancer). Previous observational findings show an adverse relationship between alcohol intake and breast cancer susceptibility, however the association was protective on EOC. Our observational data replicate previous findings, with MR estimates showing consistent direction of effect for EOC; while no evidence to support a strong link between alcohol intake and breast cancer risk. Taken altogether, the effect of alcohol on these cancers is likely small if causative at all.In Chapter 4 and 5, I performed MR to evaluate a series of modifiable risk factors on overall cancer outcomes. Using data from the UK Biobank, we constructed an aggregate phenotype allowing us to evaluate whether "modifying specific behaviour (or risk factor) will 3 alter an individual's risk of being diagnosed or dying from cancer". The proof-of-principle MR study using height is shown in Chapter 4, where MR findings are highly concordant with observational findings that taller people have increased risk of developing cancer. Findings for obesity, vitamin D and coffee intake on overall cancer outcomes are further elaborated in Chapter 5.In Chapter 5, the approach undertaken to evaluate these risk factors and cancer were each described in turn, followed by a subchapter to summarise these MR findings. Genetically higher BMI is associated with an increase of being dia...