Scientists at the University of Cambridge’s Medical Research Council (MRC) Epidemiology Unit have identified rare genetic variants, carried by one in 3,000 people, in a gene called GIGYF1, which they say has a greater impact on risk have type 2 diabetes (T2D) than any previously identified genetic effect.
The exome sequencing study, led by John Perry, PhD, program director and MRC investigator, in which more than 80,000 male UK Biobank participants took part, found that the rare GIGYF1 variants significantly increased the susceptibility to loss of the Y chromosome (LOY) increased and also increased by six times the individual risk of developing T2D. More common gene variants associated with T2D only double the risk of the disease. The team reports its findings in Nature Communications (“GIGYF1 Loss of Function Is Linked to Clonal Mosaic and Adverse Metabolic Health”) and says their findings highlight a “fascinating link between LOY and metabolic health”.
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 have 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. 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 82,277 men in the UK Biobank study, researchers at the University of Cambridge’s MRC Epidemiology Unit used this approach to identify rare 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. LOY has previously been linked to age-related diseases such as type 2 diabetes and cancer. “Loss of the Y chromosome mosaic in leukocytes is the most common form of clonal mosaic, first identified over fifty years ago,” the team noted. “It has been linked to the risk of a number of complex diseases and traits, but the biological mechanisms underlying these observations are unclear.”
However, the authors noted, “To date, genetic studies for LOY have focused on the imputed common genetic variation of the genotype array, which largely overlooks the contributions of rarer, often harmful alleles.” For their newly published study, the team conducted a genome-wide association study (GWAS) performed the exome sequence for LOY to assess the role of rare protein-coding variations. “Previous genetic studies have focused on identifying more common LOY-associated variants, which we are now expanding to include rarer, protein-encoding variations using exome sequences from 82,277 male participants in the UK Biobank.”
The results show that around 1 in 3,000 people carry rare GIGYF1 alleles with loss of function. Your risk of developing type 2 diabetes is around 30% compared to around 5% in the wider population. In addition, the study results showed that 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. “Our observations underscore a possible direct link between clonal mosaic and metabolic health,” they concluded.
As Perry noted, “Reading a person’s DNA is an effective way to identify genetic variants that increase our risk of developing certain diseases. In complex diseases such as type 2 diabetes, many variants play a role, but often only increase our risk by a tiny amount. This particular variant, although rare, has a major impact on a person’s risk. “
Co-author Nick Wareham, PhD, 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 will aim to understand how the loss of functional variants in GIGYF1 results in such a significant increase in the risk of developing type 2 diabetes. Future research will also examine other links between biomarkers of biological aging in adults and metabolic diseases.