Type 2 diabetes (T2D) is a common form of diabetes and it is one of the main threats to human health in an industrial society . The prevalence and incidence of T2D have been increasing rapidly worldwide. The etiology and pathogenesis of T2D include both genetic and environmental factors. In an attempt to investigate the underlying genetic pathogenesis of T2D, a total of 243 genetic loci, most of which are common variants, have been reported in the past decade . However, as with most polygenic diseases, the discovered genes only account for a minority of the inherited risk (heritability) of T2D (< 20%). The gap of the heritability explained by common genetic variants and the heritability identified in familial studies have been termed as ‘missing heritability’ . We are still in the process of fully dissecting the complexity of T2D. Until recently, the majority of genetic studies has been performed using array-based genotyping and genome wide association studies (GWAS), focusing on the effect of common variants. However, with the development of next generation sequencing (NGS), scientists can directly test associations between rare variants and complex diseases. The NGS heralds a new era of investigating the impact of genetic variation on T2D. This thesis provides an overview of the development of genetic aspects of diabetes, with emphasis on T2D. The etiology and pathogenesis of T2D are introduced. The current status of identification and association of genetic variants is discussed and related to the results obtained in my PhD project. Also, the methodological improvements in investigations of genetic variants made in the last decade are discussed, especially focusing on the development of NGS.
The overall aim of the thesis is to explore the underlying genetic mechanisms of T2D and related metabolic traits, with focus on risk contributions of rare variants in two well-established T2D candidate genes - GLIS3 and PPP1R3B. Common variants in both GLIS3 and PPP1R3B have been associated with several traits related to T2D as well as other forms of diabetes. In this PhD project, we applied deep sequencing on the coding regions of GLIS3 and PPP1R3B in a well-characterized Danish population which allowed us to explore the effect of rare variants. These investigations show that rare GLIS3 variants appear to have both protective and pathogenic effects on T2D. Also, rare variants present in PPP1R3B affect glycogen synthesis and lipid metabolism in the development of T2D.
In conclusion, the studies presented in this thesis provide an important contribution to the understanding of the role played by rare variants in the development of diabetes and underlying pathogenesis.