Strategies for identification and functional validation of causal genes and variants at glycaemic trait loci

Abstract

Type 2 diabetes (T2D) is a metabolic disorder that is affecting around 8% of the world’s population and can lead to serious complications. It is characterised by cells failing to respond well enough to insulin (insulin resistance) and the pancre-as not producing enough insulin to regulate blood sugar levels (beta-cell insuffi-ciency). The glycaemic traits fasting glucose (FG), 2h-glucose levels (2hGlu) and glycated haemoglobin (HbA1c) can be used to diagnose diabetes. Fasting (FI) insulin is another glycaemic trait and can be used as a proxy for insulin re-sistance that can be easily obtained in large-scale studies and help understand some of the underlying T2D pathophysiology. Both environmental and genetic factors influence the risk of developing T2D. Genome-wide association studies (GWAS) have been very successful at identifying genomic regions called loci, associated with glycaemic traits and T2D. For example, the Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) has found 242 genomic regions associated with glycaemic traits. However, variants close to each other in the genome tend to be inherited together due to linkage disequilibrium making it challenging to identify which variants are likely driving the association. Fur-thermore, most variants are lying in the non-coding part of the genome which poses a challenge to determine which genes are mediating the effect on gly-caemic traits.