The Genetics of Gene Expression and its relationship with Adiposity

Abstract

The major focus of this thesis will concern the consequences and downstream impacts of obesity and adiposity-related traits on the human body by utilising RNA-sequencing measurements from three primary tissues (Subcutaneous adipose tissue, Whole blood & Skin) and one cell line, LCLs (Lymphoblastoid cell lines). I will discuss how we can use gene expression and population genetic variation to understand the heterogeneous nature of obesity outcome in the population and to uncover the complex relationship between the eects of obesity on peripheral tissue biology, the environment and the consequences of obesity on gene regulation. First, I will examine the extent of gene expression association measured in peripheral tissues to multiple cardio-metabolic, hormonal and adiposity related measurements. I will characterise the heritability of gene expression in these four sources and discuss the tissue specicity of both trait associations and genetic eects on gene expression. Second, I will describe how BMI can act as a potent modier of gene expression in adipose tissue by modelling BMI as an exposure/environment to detect and for the rst time replicate BMIdependent eQTLs (G BMI) that are specic to adipose tissue. Lastly, I will explore the cell type heterogeneity of adipose tissue, a pertinent problem for many investigators performing gene expression based studies in bulk complex tissues. I will show how many BMI gene expression associations are driven by macrophage heterogeniety amongst samples, that cell type variability is heritable and describe examples of cis-eQTLs driven by macrophage proportion in adipose tissue.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Kerrin Small (Supervisor) & Tim Spector (Supervisor)