- Title
- Utilising genetic variants to investigate the pathophysiology of anorexia nervosa
- Creator
- Adams, Danielle Margaret
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2025
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Anorexia nervosa (AN) is a complex disorder for which few treatments are available and has significant associated morbidity and mortality. This disorder is increasing in prevalence within the population while enacting a large global burden on health systems and society more broadly. This disorder is influenced by a complex interplay of genetic and modifiable risk factors. As a result, it is often difficult to treat and much of its biology remains unknown. The emergence of genome-wide association studies (GWAS), which estimate the association between genetics variants, most often single nucleotide polymorphisms (SNPs), and a trait of interest, have enabled researchers to investigate novel disease mechanisms for AN. Polygenic effects from these variants explain a portion of trait variability and reflect the pathophysiology of these diseases. Examining the presence of these variants within a population can provide insight into the biology of AN and the genetic mechanisms responsible for disease pathophysiology. With the more recent availability of GWAS data, this thesis aims to investigate the pathophysiology of AN by leveraging the complex genetic architecture of this disorder. First, the association between glycaemic biology and AN was explored by utilising SNPs to proxy the effect of elevated lifetime exposure to glycaemic phenotypes, including fasting levels of blood glucose and insulin. Specifically, these SNPs were used as instrumental variables (IVs) which control for unmeasured confounding that may bias association estimates from observation studies. This revealed evidence that increased fasting insulin may exert a protective effect on liability to AN. Next, biological mechanisms through which AN associated variants may function were investigated using SNPs associated with altered gene and protein expression. AN associated genes which may contribute to the disease were prioritised in this transcriptome-wide association study, accelerating the future identification of genes that modulate AN risk. Finally, the genetic correlation between AN and associated metabolic traits was investigated by utilising GWAS association data. Examining local genetic correlation between metabolic traits and AN revealed regions of the genome responsible for global patterns of genetic correlation. Colocalization revealed genetic variation influencing high-density lipoprotein level and body mass index which may act through shared biological mechanisms to influence AN risk. Statistical genetics methods which utilise data capturing the association between variants and biologically meaningful traits were leveraged to build upon the growing literature exploring the pathophysiology of AN. These methods were applied to investigate novel associations between complex traits, genetic risk factors and shared genetic architecture for AN. Through these approaches, I identified specific genetic factors and modifiable traits related to metabolic regulation implicated in the risk for AN which were not previously presented in the literature.
- Subject
- anorexia nervosa; genome wide association study; Mendelian randomisation; transcriptome wide association study; local genetic correlation
- Identifier
- http://hdl.handle.net/1959.13/1519311
- Identifier
- uon:57391
- Rights
- Copyright 2025 Danielle Margaret Adams
- Language
- eng
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