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Title: The genetic mechanisms underlying human obesity
Author: Clark, Stephen James
ISNI:       0000 0004 2741 7869
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Obesity is becoming one the leading causes of mortality in the western world. Although environment is a factor in its development, it is highly heritable and despite a number of genes that have been found to be associated to the disease its genetics are still poorly understood. Discovery of genetic pathways that influence obesity risk can provide a better understanding of the pathophysiology of the disease and identify possible pharmacological targets for its treatment. This project was designed to investigate possible genetic associations between five candidate genes and severe obesity in both adult and child French Caucasians (n=2,822). Tag SNPs were chosen along with a selection of common SNPs not in the HapMap database and genotyped using Sequenom iPLEX assays. Putative associations were discovered to obesity in three genes, SIRT1 (corrected p-values: 0.034, 0.019), APLN (corrected p-value: 0.017) and IL11 (corrected p-value: 0.016), although associations do not withstand genome-wide correction. SIRT1 and IL11 SNPs were subsequently genotyped within a family cohort for which transcription data in adipose tissue was available. In this cohort, SIRT1 genotypes were nominally associated with BMI (corrected p-values: 0.014, 0.019, 0.014) and a significant difference in expression levels of the gene was observed between lean and obese individuals (p=1.6x10-35) providing suggestive evidence of a role of this gene in the development of obesity. Expression and genotypes of another gene, IRS1 were also analysed and although no significant associations to obesity were found, an association between SNP variation and gene expression was discovered (corrected p-value: 1.0x10-5). Another aim of this project was to investigate the possibility that DNA methylation influences obesity risk. Firstly, a method for the measurement of the quantitative trait of DNA methylation status at individual CpG sites was developed using direct sequencing. Next, methylation in the leptin gene CpG island was measured in a subset of 184 case-control samples and a nominal association was discovered between the quantitative measurement of methylation at a single CpG site and obesity (p=0.013). In summary, putative associations to obesity have been discovered with genetic variants as well as transcription levels and CpG methylation. Replication in other populations is required in order to confirm these associations.
Supervisor: Walley, Andrew ; Froguel, Philippe Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral