Genetic etiology of type 2 diabetes
|PhD ceremony:||Mr M.R. (Mike) Erdos|
|When:||March 18, 2015|
|Supervisors:||prof. dr. C. (Cisca) Wijmenga, M.H. Hofker, F.S. Collins|
|Where:||Academy building RUG|
|Faculty:||Medical Sciences / UMCG|
Type 2 diabetes (T2D) is a common complex metabolic disorder with both genetic and environmental influences. The heritability of T2D in the general population has been estimated to be ~26%. Efforts to identify the genetic basis of T2D in the past several years include candidate gene association analyses and genome-wide association studies (GWAS). These studies have shown that most of the T2D associated loci are located in non-coding and intergenic regions of the genome suggesting that gene regulatory regions play an important role in T2D susceptibility.
This thesis describes genetic association studies that identify candidate genes associated with T2D and that genome-wide association analysis is valuable to identify genetic loci involved in T2D. GWAS in normal populations can identify genetic loci for T2D-related quantitative traits such as fasting glucose. However, these GWAS often do not identify the specific gene in the associated locus. The identification of the causal gene in these T2D association loci requires functional analyses of genes implicated as demonstrated by the increased expression of the melatonin receptor 1B gene in subjects at risk for T2D. Further insights into causal variants in T2D susceptible loci can be determined by identification of key regulatory elements in epigenomic analysis in pancreatic islets. Beyond GWAS the functional analysis of variants regulating gene expression in additional disease relevant tissues such as muscle and adipose can identify the causal gene in T2D associated loci. GWAS is a valuable tool when combined with functional dissection of T2D associated loci to discover appropriate therapeutic targets.