Scientists at the University of Cambridge have identified rare genetic variants – carried by one in 3,000 people – that have a greater impact on the risk of developing type 2 diabetes than any previously identified genetic effect.
Type 2 diabetes is thought to be caused in part by inherited genetic factors, but many of these genes are still unknown. Previous large-scale studies relied on efficient “array genotyping” methods to measure genetic variation across the genome. This approach usually does a good job of capturing the common genetic differences between people, even though they individually cause little increase in diabetes risk.
Recent advances in technology have enabled more comprehensive genetic measurement by reading the full DNA sequences of over 20,000 genes that code for proteins in humans. Proteins are essential molecules that enable our body to function. In particular, this new approach has enabled, for the first time, a large-scale approach to studying the effects of rare genetic variants on various diseases, including type 2 diabetes.
Using data from more than 200,000 adults in the UK Biobank study, researchers from the Epidemiology Unit of the Medical Research Council (MRC) at the University of Cambridge used this approach to identify genetic variants associated with loss of the Y chromosome . This is a well-known biomarker of biological aging that occurs in a small percentage of circulating white blood cells in men and indicates a weakening of the body’s cellular repair systems. This biomarker has previously been linked to age-related diseases such as type 2 diabetes and cancer.
In the results published today in Nature Communications, the researchers identified rare variants in the GIGYF1 gene that significantly increase a person’s susceptibility to loss of the Y chromosome and also increase a person’s risk of developing type 2 diabetes by six-fold. In contrast, common variants associated with type 2 diabetes result in a much more modest increase in risk, typically much less than two-fold.
Around 1 in 3,000 people carry such a genetic variant of GIGYF1. Your risk of developing type 2 diabetes is around 30% compared to around 5% in the wider population. In addition, people who wore these variants had other signs of aging, including weaker muscle strength and more body fat.
It is believed that GIGYF1 controls the signaling of insulin and cell growth factors. The researchers say their results identify this as a potential target for future studies to understand the common links between metabolic and cellular aging and inform future treatments.
Reading out a person’s DNA is an effective way to identify genetic variants that increase our risk of developing certain diseases. Many variants play a role in complex diseases such as type 2 diabetes, but often only increase our risk by a tiny amount. This particular variant, while rare, has a major impact on a person’s risk. “
Dr. John Perry, MRC Epidemiology Unit and senior author of the article
Professor Nick Wareham, Director of the MRC Epidemiology Unit, added: “Our results underscore the exciting scientific potential of sequencing the genomes of very large numbers of people. We are confident that this approach will usher in a rich new era of informative genetic discovery that will help us better understand common diseases such as type 2 diabetes. In this way we may be able to offer better options for treating – or even preventing – the disease. “
Ongoing research aims to understand how the loss of functional variants in GIGYF1 leads to such a significant increase in the risk of type 2 diabetes. Her future research will also explore other links between adult biological aging biomarkers and metabolic diseases.
Source:
Journal reference:
Zhao, Y., et al. (2021) The loss of function of GIGYF1 is linked to clonal mosaic and adverse metabolic health. Nature communication. doi.org/10.1038/s41467-021-24504-y.
