Type 2 diabetes is caused by defective insulin secretion in the presence of insulin resistance. It usually occurs in late adulthood and is associated with high body mass index (BM I). Genome-wide association studies (GWASs) have identified more than 200 genetic variants associated with metabolic traits, including more than 100 associated with type 2 diabetes, obesity and insulin resistance. This number is increasing as larger meta-analyses of GWASs are performed. However, there has been a bottleneck in translating GWAS findings into improved knowledge of biology and disease mechanisms. This thesis presents a series of post-GWAS strategies to find the genetic background between type 2 diabetes and metabolic traits, to use known genetic variants to understand some of the mechanisms that lead to insulin resistance and its relationship with type 2 diabetes and cardio vascular disease and to find the precise genes involved for most of the variants using gene expression data. Chapter 1 is an introduction to the discovery of genes associated with type 2 diabetes risk and metabolic traits from genome-wide association studies and some of the recent mechanistic insights derived from the genetic association studies about type 2 diabetes and its link with metabolic traits and diseases. Chapter 2 presents the largest genome-wide association study of birth weight. Five novel common genetic variations were identified to influence birth weight, in addition to an interesting finding about the genetic links between fetal growth and postnatal growth and metabolism. Chapter 3 describes a study designed to identify the genetic link between birth weight and type 2 diabetes. This study used a novel approach to account for opposing effect of maternal and fetal genotypes and found sets of type 2 diabetes genes that influence birth weight either directly through the fetal genotype or indirectly through the maternal genotype. Chapter 4 describes a study that uses Mendelian randomisation approaches to test the causal association between adiponectin and risk of insulin resistance , I and type 2 diabetes. This largest study of adiponectin did not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes. Chapter 5 presents a study designed to utilise metabolic features of monogenic forms of insulin resistance in a novel approach to characterise less penetrant variants associated with common form of insulin resistance. This study identified an interesting cluster of 11 common variants consistent with a "polygenic lipodystrophy" phenotype characterised by an increased risk of type 2 diabetes, cardio-vascular disease and hypertension but with reduced BMI. Chapter 6 describes the largest study designed to identify common genetic variants influencing the expression levels of their neighbour genes ('cis' hits) and genes far from them (,trans' hits). These 'trans' hits provided insights into the downstream effects of complex trait associated SNPs, such as altered TAGAP and LDLR expression in celiac disease and cholesterol metabolism, respectively, and altered C1 QB and type 1 interferon (IFN-a) gene expression in systemic lupus erythematosus. Chapter 7 discusses the research findings and limitations from previous chapters, describes future research plans in the genetics of insulin resistance and type 2 diabetes and presents conclusions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:606688 |
| Date | January 2013 |
| Creators | Yaghootkar, Hanieh |
| Publisher | Exeter and Plymouth Peninsula Medical School |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0017 seconds