Researchers have identified loss-of-function GIGYF1 variants that contribute more to the risk of loss of Y chromosome and type 2 diabetes than any other previously identified variants.
Loss of the Y chromosome (LOY) in white blood cells is a marker of biological ageing. It is the most common form of clonal mosaicism, where somatic genetic mutations give rise to more than one cellular population with distinct genomes. More than 150 common genetic variants have been identified to predispose individuals to LOY. These include genes involved in maintaining the cell cycle and DNA damage responses, implicating the role of genomic instability in LOY.
Biological mechanisms underlying LOY onset and pathology are thought to be shared with other complex diseases. This may explain why LOY raises the risk of age-related complex diseases, such as type 2 diabetes (T2D). Consequently, identifying genetic variants associated with LOY may simultaneously detect those contributing to the susceptibility of other diseases.
In this study published in Nature Communications, researchers at the University of Cambridge investigated exome sequence data from over 200,000 adults in the UK Biobank to identify LOY-associated genetic variants. Previous genetic studies on LOY have used genotype arrays with imputed common gene variants. However, this approach overlooks rare deleterious alleles contributing to disease risk. In contrast, whole-exome sequencing data enabled these researchers to identify rare, large-effect protein-coding variants associated with LOY.
Gene burden analysis showed that rare loss-of-function variants in CHEK2 are significantly associated with LOY. This result verified the findings of previous LOY genetic studies.
GIGFY1 – a link between LOY and T2D?
On the other hand, this study revealed associations between rare loss-of-function GIGYF1 variants and LOY for the first time. These variants were associated with a 5-fold greater risk of LOY than any other previously identified gene variant.
GIGYF1 is known to play various roles in insulin and growth factor signalling, which may affect metabolic health. Accordingly, the researchers further investigated the association of these GIGYF1 variants with 17 metabolic traits. Strikingly, the variants associated with a 6-fold higher risk for T2D. In comparison, most rare variants only double the risk of T2D, while common variants increase risk by less than 1.5-fold.
These findings illuminate a common genetic variant underlying LOY and T2D risk, implicating a direct link between clonal mosaicism and metabolic health. Further experimental studies may provide novel mechanistic insights pertaining the role of GIGYF1 in both diseases. This study also illustrates the power of using exome data to identify rare, large-effect risk variants. Crucially, these variants may inform the development of novel treatments for complex diseases.
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