by University of Cambridge
Scientists at the University of Cambridge
have identified rare genetic variants—carried by one in 3,000 people—that have
a larger impact on the risk of developing type 2 diabetes than any previously
identified genetic effect.
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 depended 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. Proteins are essential molecules
that enable our bodies to function. 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 more than 200,000
adults in the UK Biobank study, researchers from the Medical Research Council
(MRC) Epidemiology Unit at the University of Cambridge used this approach to identify
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. This biomarker has been previously linked to age-related
diseases such as type 2 diabetes and cancer.
In results published today in Nature
Communications, the researchers identified rare variants in the gene GIGYF1
that substantially increase susceptibility to loss of the Y chromosome, and
also increase an individual's risk of developing type 2 diabetes six-fold. In
contrast, common variants associated with type 2 diabetes confer much more
modest increases in risk, typically much lower than two-fold.
Around 1 in 3,000 individuals carries such
a GIGYF1 genetic variant. Their risk of developing type 2 diabetes is around
30%, compared to around 5% in the wider population. In addition, 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 signaling. 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.
Dr. John Perry, from the MRC Epidemiology
Unit and a senior author on the paper, said: "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."
Professor Nick Wareham, 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 lead to such a substantial increase in
the risk of developing type 2 diabetes. Their future research will also examine
other links between biomarkers of biological aging in adults and metabolic
disorders.