An extensive genetic analysis involving more than 900,000 people has revealed that specific DNA segments composed of short, repetitive sequences increase in length and instability as people age. The research showed that common inherited variants can alter the pace of this expansion by up to fourfold. Some of these expanded sequences are linked to serious diseases such as kidney failure and liver disease.
Expanded DNA repeats have long been known to cause over 60 inherited disorders, including Huntington’s disease, myotonic dystrophy, and certain forms of ALS. Because most individuals carry DNA repeats that lengthen gradually, understanding what drives these changes is crucial. This study provides a comprehensive look at how widespread repeat expansion is and identifies many genes that govern its rate, offering potential paths for therapies that target these controlling mechanisms.
The team from UCLA, the Broad Institute, and Harvard Medical School evaluated whole-genome sequencing data from 490,416 UK Biobank participants and 414,830 individuals from the All of Us Research Program. They created computational methods capable of detecting and measuring DNA repeat lengths and their instability using standard sequencing results. By examining more than 356,000 polymorphic repeat sites, the team tracked how the lengths of these repeats changed with age in blood cells and pinpointed genetic variants influencing expansion speed. They also correlated these expansions with numerous disease outcomes, revealing previously unknown disease associations.
The analysis showed that DNA repeats in blood cells typically lengthen with age. At 29 genomic locations, inherited genetic differences affected the rate of expansion, sometimes leading to up to a fourfold contrast between people with low versus high risk. The same DNA repair genes were found to stabilize certain repeats but destabilize others. Notably, expansions within the GLS gene—seen in about 0.03% of individuals—were linked to a 14-fold higher risk of severe kidney disease and a threefold higher risk of liver disease.
These findings suggest that tracking DNA repeat length in blood could serve as a biomarker for testing potential therapies aimed at slowing repeat expansion in conditions like Huntington’s disease. “We found that most human genomes contain repeat elements that expand as we age,” said Margaux L. A. Hujoel, lead author of the study published in Nature. "The strong genetic control of this expansion, with some individuals' repeats expanding four times faster than others, points to opportunities for therapeutic intervention. These naturally occurring genetic modifiers show us which molecular pathways could be targeted to slow repeat expansion in disease."
Publication details: Hujoel, M.L.A., Handsaker, R.E., Tang, D. et al. Insights into DNA repeat expansions among 900,000 biobank participants. Nature (2026). https://doi.org/10.1038/s41586-025-09886-z
Expanded DNA repeats have long been known to cause over 60 inherited disorders, including Huntington’s disease, myotonic dystrophy, and certain forms of ALS. Because most individuals carry DNA repeats that lengthen gradually, understanding what drives these changes is crucial. This study provides a comprehensive look at how widespread repeat expansion is and identifies many genes that govern its rate, offering potential paths for therapies that target these controlling mechanisms.
The team from UCLA, the Broad Institute, and Harvard Medical School evaluated whole-genome sequencing data from 490,416 UK Biobank participants and 414,830 individuals from the All of Us Research Program. They created computational methods capable of detecting and measuring DNA repeat lengths and their instability using standard sequencing results. By examining more than 356,000 polymorphic repeat sites, the team tracked how the lengths of these repeats changed with age in blood cells and pinpointed genetic variants influencing expansion speed. They also correlated these expansions with numerous disease outcomes, revealing previously unknown disease associations.
The analysis showed that DNA repeats in blood cells typically lengthen with age. At 29 genomic locations, inherited genetic differences affected the rate of expansion, sometimes leading to up to a fourfold contrast between people with low versus high risk. The same DNA repair genes were found to stabilize certain repeats but destabilize others. Notably, expansions within the GLS gene—seen in about 0.03% of individuals—were linked to a 14-fold higher risk of severe kidney disease and a threefold higher risk of liver disease.
These findings suggest that tracking DNA repeat length in blood could serve as a biomarker for testing potential therapies aimed at slowing repeat expansion in conditions like Huntington’s disease. “We found that most human genomes contain repeat elements that expand as we age,” said Margaux L. A. Hujoel, lead author of the study published in Nature. "The strong genetic control of this expansion, with some individuals' repeats expanding four times faster than others, points to opportunities for therapeutic intervention. These naturally occurring genetic modifiers show us which molecular pathways could be targeted to slow repeat expansion in disease."
Publication details: Hujoel, M.L.A., Handsaker, R.E., Tang, D. et al. Insights into DNA repeat expansions among 900,000 biobank participants. Nature (2026). https://doi.org/10.1038/s41586-025-09886-z