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Rare Mutations Associated With Significantly Higher Risk of Type 2 Diabetes in New Study

NEW YORK – Researchers at the University of Cambridge and the Broad Institute have identified rare genetic variants that confer a larger risk of developing type 2 diabetes on carriers than any other previously identified variants to date.

In a paper published on Wednesday in Nature Communications, the researchers said they looked at mosaic loss of chromosome Y, or LOY, in leukocytes, the most common form of clonal mosaicism and a trait associated with risk of a variety complex diseases and traits. LOY is caused by dysregulation in cell-cycle and DNA damage response pathways, the researchers noted. While previous genetic studies have looked at common variants associated with LOY, this study analyzed rarer, protein-coding variation using exome sequences from 82,277 male participants in the UK Biobank.

From this analysis, the researchers found that loss of function in the CHEK2 and GIGYF1 genes reached exome-wide significance. Loss-of-function variants in CHEK2 had previously been implicated with LOY as the most common frameshift variant, and accounted for 76 percent of loss-of-function carriers.

Rare alleles in GIGYF1, however, had not previously been implicated in any complex trait. But GIGYF1 is named after its known binding to growth factor receptor-bound protein 10 and interacts with both the insulin and IGF1 receptors, the researchers explained. Therefore, they hypothesized that loss-of-function alleles in this gene could also affect metabolic health.

Indeed, when they tested GIGYF1 burden across 17 metabolic-health related traits in men and women, they found that GIGYF1 loss of function was associated with higher susceptibility to type 2 diabetes and higher acute and longer-term average levels of glycemia in non-diabetic individuals.

Of the 64 carriers of GIGYF1 loss-of-function alleles in the study, 19 (or 30 percent) had type 2 diabetes, compared to 7.1 percent in the wider population of the UK Biobank.

Further, GIGYF1 loss-of-function carriers in this study exhibited a sixfold higher susceptibility to LOY, a burden signal that combined the effects of 27 rare variants. These alleles were also associated with additional markers of adverse metabolic health, such as higher fat mass, lower serum IGF1 levels, and lower handgrip strength.

"For complex diseases such as type 2 diabetes, many variants play a role, but often only increasing our risk by a tiny amount," corresponding author and Cambridge researcher John Perry said in a statement. "This particular variant, while rare, has a big impact on an individual's risk."

These associations were also mirrored by a common variant nearby that's associated with the expression of GIGYF1, the researchers said, adding that these observations highlighted a potentially direct connection between clonal mosaicism and metabolic health.

"Our findings highlight the exciting scientific potential of sequencing the genomes of very large numbers of people," added Nicholas Wareham, director of Cambridge's MRC Epidemiology Unit and co-author on the paper. "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."

The researchers concluded that GIGYF1 and the related protein GIGYF2 are implicated in translational repression and translation-coupled mRNA decay, suggesting that they may have biological roles beyond insulin and IGF-1 receptor signaling.

"Although GIGYF1 is broadly expressed, the lack of associations in our data with some established IGF-1-related traits, such as birth weight and adult height, might reflect tissue or developmental specificity in its effects," the authors wrote. "We anticipate that future experimental work will shed light on these questions to better understand the links between clonal mosaicism and metabolic health."

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