Common and Rare Genetic Risk in Type 2 Diabetes in South Asian Individuals

Type 2 diabetes, a common medical condition in which the body’s blood sugar levels are too high, is a major cause of death and major medical problems (like kidney and eye disease) in the UK and worldwide. It is between 2 and 4 times more common in South Asian ancestry individuals than other ancestral groups(1), but the reasons for this are not clear. Lots of research suggests genetics (the blueprints our bodies are built on, containing information inherited from parents) plays a significant role in this.

Two extremes of genetic risk may contribute to the increased chance of South Asian ancestry individuals developing type 2 diabetes. “Rare” genetic variants in a single gene (the unit of genetic information telling the body how to make a single protein, which performs a function like moving sugar in and out of cells) may explain some of this risk. “Common” variation in hundreds of genes within an individual may also play a role – this information can be captured in a “polygenic risk score”. These scores have been shown to improve prediction of type 2 diabetes and its complications in British Pakistani and Bangladeshi individuals in the Genes & Health study, both as “summary”-level scores, and as “partitioned” scores which describe one specific element of disease risk, such as obesity(2). It is unclear how these two forms of risk might interact – in other diseases like breast cancer, for example, high polygenic risk scores make it more likely people with specific “rare” genetic variants develop the disease(3). We will explore whether this is also the case in type 2 diabetes.

We will also explore how a genetic phenomenon called autozygosity increases type 2 diabetes risk – this has been shown to be the case in British Pakistani and Bangladeshi individuals in the Genes & Health study(4), but the reasons underlying this link remain unclear. Autozygosity occurs when both an individual’s copies of a long segment of genetic code can be traced back to the same recent ancestor. As well as being at higher risk of type 2 diabetes, South Asian individuals tend to have higher levels of autozygosity than other ancestral groups. We will explore whether autozygosity is linked to specific subtypes of diabetes (like diabetes related to obesity, or resistance to insulin), and whether it is linked to common, rare, or both types of genetic variation contributing to diabetes risk. In the Genes & Health study, for example, we find that a 6.25% increase in autozygosity is linked to being diagnosed with type 2 diabetes 2.5 years earlier in life, and with a most recent height 1.8cm shorter. We will build on this finding by exploring growth trajectories associated with autozygosity in early life.

We hope our results will help improve the understanding of how diabetes develops in an under-studied and under-represented population, and ultimately aid to better prevention and treatment options for South Asian individuals at risk of, or living with, type 2 diabetes.