Applying genetic epidemiology to explore sex-specific causes, correlations and consequences of obesity

Obesity has considerable consequences on global health. Yet, it is relatively unexplored if the causes and consequences of obesity and obesity-related diseases differ between men and women. The increased scope of genetic studies provides an opportunity to leverage genetic data to characterise sex-specific epidemiological relationships using methods less prone to reverse causation and confounding, such as Mendelian randomisation. Thus, I aimed to investigate the sex-specific causes and consequences of obesity using genetic epidemiology, as well as to identify potential disease-mediating genes in two common obesity-related female reproductive diseases: polycystic ovary syndrome and miscarriage. In my first research chapter, I use Mendelian randomisation to investigate the sex-specific effects of obesity on leading causes of death from non-communicable diseases, before comparing the men- and women-specific effect estimates. My results indicate that the disease risk arising from obesity differs between the sexes for several diseases, including type 2 diabetes, renal failure, and chronic obstructive pulmonary disease. I then proceed to perform sex-stratified genome-wide association studies of 2,623 unique proteins and compare the effect estimates of the genetic variants between the sexes. Using these data, I compare the effects of proteins on obesity and cardiometabolic diseases between men and women. My results in this chapter indicate that up to 15% of protein-associated genetic variants may have different effects in the two sexes. I further identify seven proteins with sexually heterogeneous effects on obesity in men versus women, including two proteins – kynureninase and N-terminal pro b-type natriuretic peptide – with seemingly opposite effects in men compared to women. However, sensitivity analyses indicated that my results may be affected by poor specificity in the original protein measurements. Finally, in my third research chapter, I use colocalisation to highlight potential disease-mediating genes in polycystic ovary syndrome and recurrent miscarriage. While I was not able to identify any potential disease-mediating genes for recurrent miscarriage, I identify eleven genes and proteins with evidence of colocalising with risk of polycystic ovary syndrome. My thesis demonstrates that causal relationships in cardiometabolic disease can differ between the sexes, and emphasises the importance of investigating sex-specific effects. Furthermore, my results highlight several genes and proteins that may contribute to obesity and obesity-related diseases. Although their clinical utility will need to be established in future studies, several of these genes and proteins hold promise for use as biomarkers or for targeting by drugs to improve the health of both men and women.