The Molecular Genetics of Type 2 Diabetes: Past, Present and Future


Type 2 diabetes is a metabolic disorder which is characterized by elevated blood glucose levels. This common disease affects more than 170 million individuals worldwide. It is a complex disease caused by a combination of multiple genetic factors and environmental exposures. Early attempts to decipher the genetics of type 2 diabetes achieved limited success with only a handful of loci identified showing convincing association. However, with the advent of genome‐wide association studies, much progress has been made in recent years in understanding the genetics of type 2 diabetes. Over a dozen novel susceptibility loci showing consistent and robust associations across different populations have been identified, with the risk associated with the majority of these loci exerting their effect through pancreatic β‐cell dysfunction, leading to impairment in insulin secretion, in the patho‐physiology of diabetes.

Key concepts

  • Type 2 diabetes is characterized by hyperglycaemia (elevated blood glucose level) as a consequence of the body's inability to maintain blood glucose homeostasis.

  • This common disease affects more than 170 million individuals worldwide, and this has been projected to increase to over 360 million by 2030.

  • It is a polygenic disease with many genetic variants, each contributing a modest effect with additional gene–gene and gene–environment interactions adding further complexity.

  • As with many other complex diseases, the molecular pathways or mechanisms underlying the development of type 2 diabetes have remained poorly understood.

  • Genetic studies of diseases have traditionally relied on two methods to discover the responsible genes: whole genome linkage mapping and candidate gene association studies.

  • Genetic studies of the past were largely unsuccessful with only a handful of loci showing convincing association with type 2 diabetes.

  • Genome‐wide association study is a comprehensive and unbiased approach of interrogating a large number of genetic markers across the genome to identify statistical association between genetic variants and phenotypes.

  • In contrast to linkage studies, it is usually carried out in unrelated individuals, and unlike candidate gene studies, it does not require any prior supposition of the biological function of genes or pathogenesis of the disease.

  • The findings from genome‐wide association studies have made some advances in our understanding and knowledge of the genetic basis of this common disease, and it has also implicated the importance of β‐cell dysfunction and impairment in insulin secretion in the patho‐physiology of type 2 diabetes.

  • Cumulatively, all the type 2 diabetes susceptibility SNPs that have been identified account for only a small proportion of the heritability (approximately 10%); with the majority of the genetic predisposition remaining unexplained, indicating that much still remains to be discovered and understood of the genetic basis of this complex disease.

Keywords: type 2 diabetes; complex diseases; linkage mapping; genome‐wide association studies; single nucleotide polymorphisms; International HapMap Project

Figure 1.

This chart shows the progress in the search for type 2 diabetes‐associated genes. The x‐axis shows the year from 2000 to 2008, and y‐axis depicts the number of genes identified. The genes are highlighted according to the method used in their discovery (red for linkage, green for candidate gene association and blue for genome‐wide association studies). The genes associated with fasting glucose levels are not shown in this chart.



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Further Reading

Lyssenko V and Groop L (2009) Genome‐wide association study for type 2 diabetes: clinical applications. Current Opinion in Lipidology 20: 87–91.

Majithia AR and Florez JC (2009) Clinical translation of genetic predictors for type 2 diabetes. Current Opinion in Endocrinology, Diabetes and Obesity 16: 100–106.

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Ridderstrale M and Groop L (2009) Genetic dissection of type 2 diabetes. Molecular and Cellular Endocrinology 297: 10–17.

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Tan, Jonathan T, Chia, Kee Seng, and Ku, Chee Seng(Dec 2009) The Molecular Genetics of Type 2 Diabetes: Past, Present and Future. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021994]