Is one faulty gene responsible for type 2 diabetes? No. Type 2 diabetes mellitus (T2DM) is polygenic. The risk is built from many common variants, each of small effect, and no single variant decides whether the disease appears. T2DM is made by both genetic and environmental factors. Relatives share part of their genes, and the disease results from genes and environment together, as the risk factors note sets out. The disease runs in families.
How much does each variant add?
More than 50 genes are known for T2DM. The size of each variant’s effect is measured as an odds ratio, and an odds ratio of 1 means no effect. In T2DM the odds ratios are mostly close to 1. The largest reach up to about 1.4.
If most of these variants are common and weak, the next question is whether one of them is enough.
Is one variant enough?
No. The effect of any one variant is so small that T2DM on genetic grounds alone requires several polymorphisms at once. Sometimes as many as 10 susceptibility genes are required.
A variant that shifts the odds this little cannot cause the disease alone. Even where a variant is common, it is not sufficient to cause the disease by itself, and the reason is its low effect size. The disease cannot be predicted from a single genotype.
Does a small effect mean a small genetic share?
If each variant is so weak, is the genetic share small too? It is not. The small effect of each variant must not be read as a small overall genetic influence. Twin studies give heritability estimates that range widely by population, from roughly 50% to about 72% of the variation in risk. Whatever the exact figure, the genetic contribution as a whole is substantial, even though it is spread across many weak variants.
The small effect of each known variant says little about the size of the total.
How is type 1 diabetes different?
The genetic architecture of T2DM differs from that of type 1 diabetes (T1DM), and the difference lies in the size of each variant’s effect. In T1DM some genes and their polymorphisms are quite common, yet they carry an odds ratio above 2. The strongest of them belong to the HLA class II genes, and this one region is estimated to account for a large share of the familial clustering of T1DM.
Why would these genes weigh so much? HLA class II genes shape immune self-tolerance. Self-tolerance is built largely in the thymus, where autoreactive T cells are deleted. This depends on class II molecules displaying self-peptides on thymic epithelial cells, so these genes influence which self-reactive cells are removed. Type 1 diabetes works the other way round from T2DM, with a few genes weighing much more.
Genes set how likely the disease is, but what does it look like when it first shows in a person?