Genetics of type 2 diabetes
Until recently the genetic variation and genes involved in type 2 diabetes were very poorly characterised. Traditionally genetic studies focused on the collection and characterisation of multi-generation families but type 2 diabetes occurs in older age, making the collection of affected families difficult – the parents of most patients have died and most offspring have yet to develop the condition. Furthermore the increasing prevalence of type 2 diabetes over one or two generations proves that the changing environment has a strong role to play in type 2 diabetes risk – gene frequencies do not change appreciably in 1 or 2 generations, and certainly not those that influence a disease of largely post reproductive age. Two major developments mean that we now know of 65 regions of the human genome that influence type 2 diabetes risk. First, in 2007 genome wide association studies (GWAS) became possible. These studies provided scientists with the ability to analyse 100,000s of single nucleotide variants (the simplest and most abundant type of DNA marker) in a single experiment. Second, scientists realised that they would have to work together and combine case-control studies to achieve the very large sample sizes that provided adequate statistical power to identify the subtle effects of common genetic risk factors.
These developments have resulted in the latest study of 35,000 European type 2 diabetes cases and 115,000 controls.
History and heritability of type 2 diabetes genetics.
Before trying to identify genes, geneticists tend to perform twin or family studies in attempts to quantify the relative contributions of genes (heritability) and environment. Comparing disease concordance in identical twins to same sex non-identical twins is a powerful approach. However, the twin studies performed for type 2 diabetes provide very different estimates of concordance in twin pairs. For monozygotic twin pairs these estimates range from 36% in a study of Finnish twins to 83% in a Japanese study. Equivalent figures for dizygotic twins were 16% and 40% respectively. One of the most robust studies used 44 pairs of identical twins where one twin had developed type 2 diabetes. After following up for 15 years 76% of the initially non-diabetic twins had developed the condition. It is this contributor’s opinion that studies of heritability in type 2 diabetes are just too variable to provide a meangingful figure – it could be as low as 20% or as high as 70%.
During the 1990s and early 2000s linkage studies aimed to identify large regions of the genome shared by affected family members more often than expected by chance. Typically linkage studies were based on affected sib pairs and the identification of regions of the genome shared more often than the 50% expected if no gene existed. However linkage studies were limited by their lack of resolution – regions of the genome shared between close family relatives tend to be large and contain many 100s of genes.
Candidate gene studies
The lack of resolution provided by linkage studies forced researchers to turn attention to candidate genes and association studies. These studies typically involved several 100 cases and several 100 controls and the analysis of one or more key polymorphisms in candidate genes. These studies were not very successful because, as we later learned, sample sizes were too small to provide robust statistics, and they relied heavily on already having a good idea of the genes most likely to be involved.
Successes from linkage and candidate gene approaches were limited largely to the following:
- A candidate gene study combined with meta-analysis of multiple case control studies identified the Pro12Ala variant in the PPARG gene (Altshuler et al NG 2000).
- A candidate gene study combined with meta-analysis of multiple case control studies identified the E23K variant in the KCNJ11 gene (Gloyn et al Diabetes 2003).
- A systematic screen of variants in a region of linkage on chromosome 10 identified a common intronic variant in the TCF7L2 gene (Grant et al Nature genetics, 2006).
^ Morris, A. P., B. F. Voight, et al. "Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes." Nat Genet 44(9): 981-90.
^ Kaprio J et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population based cohort of twins in Finland. Diabetologia 1992;35:1060-7.
^ Committee on Diabetic Twins, Japan Diabetes Society. Diabetes mellitus in twins: a cooperative study in Japan. Diabetes Res Clin Pract 1988;5:271-80.
^ Medici F et al. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 1999;42:146-50