Scientists at the University of Cambridge Medical Research Council (MRC) Epidemiology Unit have identified rare genetic variants—carried by one in 3,000 people—in a gene known as GIGYF1, which they say have a greater impact on the risk of developing type 2 diabetes (T2D) than any previously identified genetic effect.

The exome sequencing study, headed by John Perry, PhD, program leader and MRC investigator, and involving more than 80,000 male UK Biobank participants, found that the rare GIGYF1 variants substantially increased susceptibility to loss of the Y chromosome (LOY), and also increased by sixfold an individual’s risk of developing T2D. More common gene variants linked with T2D only increase disease risk twofold. Reporting their findings in Nature Communications (“GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health”) the team says their findings highlight an “intriguing link between LOY and metabolic health.”

Type 2 diabetes is thought to be driven in part by inherited genetic factors, but many of these genes are yet unknown. Previous large-scale studies have relied on efficient “array genotyping” methods to measure genetic variations across the whole genome. This approach typically does a good job at capturing the common genetic differences between people, though individually these each confer only small increases in diabetes risk.

Recent technical advances have allowed more comprehensive genetic measurement by reading the complete DNA sequences of over 20,000 genes that code for proteins in humans. In particular, this new approach has allowed for the first time a large-scale approach to study the impact of rare genetic variants on several diseases, including type 2 diabetes.

By looking at data from 82,277 men in the UK Biobank study, researchers from the MRC Epidemiology Unit at the University of Cambridge used this approach to identify rare genetic variants associated with the loss of the Y chromosome. This is a known biomarker of biological aging that occurs in a small proportion of circulating white blood cells in men and indicates a weakening in the body’s cellular repair systems. LOY has been previously linked to age-related diseases such as type 2 diabetes and cancer. “Mosaic loss of the Y chromosome in leukocytes is the most common form of clonal mosaicism, first noted over fifty years ago,” the team noted. “It has been associated with the risk of a number of complex diseases and traits, however, the biological mechanisms underpinning these observations are unclear.”

However, as the authors noted, “To date, genetic studies for LOY have focused on genotype-array imputed common genetic variation, which largely misses the contributions of rarer, often more deleterious, alleles.” For their newly reported study, the team carried out an exome-sequence genome-wide association study (GWAS) for LOY, to evaluate the role of rare protein-coding variations. “Previous genetic studies have focused on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants.”

The results indicate that around 1 in 3,000 individuals carries rare loss of function GIGYF1 alleles. Their risk of developing type 2 diabetes is around 30%, compared with around 5% in the wider population. In addition, the study results showed that people who carried these variants had other signs of more widespread aging, including weaker muscle strength and more body fat.

GIGYF1 is thought to control insulin and cell growth factor signalling. The researchers say their findings identify this as a potential target for future studies to understand the common links between metabolic and cellular aging, and to inform future treatments. “Our observations highlight a potential direct connection between clonal mosaicism and metabolic health,” they concluded.

As Perry noted, “Reading an individual’s DNA is a powerful way of identifying genetic variants that increase our risk of developing certain diseases. For complex diseases such as type 2 diabetes, many variants play a role, but often only increasing our risk by a tiny amount. This particular variant, while rare, has a big impact on an individual’s risk.”

Co-author Nick Wareham, PhD, director of the MRC Epidemiology Unit, added: “Our findings highlight the exciting scientific potential of sequencing the genomes of very large numbers of people. We are confident that this approach will bring a rich new era of informative genetic discoveries that will help us better understand common diseases such as type 2 diabetes. By doing this, we can potentially offer better ways to treat—or even to prevent—the condition.”

Ongoing research will aim to understand how the loss of function variants in GIGYF1 leads to such a substantial 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 disorders.

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