A large-scale genetic analysis of nearly a million people has shown that DNA repeat sequences expand as individuals age, with common genetic variants influencing the speed of this process by up to four times. Researchers identified links between these expansions and increased risks of severe kidney and liver diseases. The findings highlight opportunities for new treatments targeting age-related DNA instability.
A collaborative team from UCLA, the Broad Institute, and Harvard Medical School conducted a comprehensive study using whole genome sequencing data from 490,416 UK Biobank participants and 414,830 from the All of Us Research Program. They developed computational tools to measure DNA repeat lengths and instability across 356,131 variable sites in the human genome, focusing on changes in blood cells over time.
The analysis revealed that most people carry DNA repeats that gradually lengthen with age. Inherited genetic variants in 29 genomic regions can alter expansion rates dramatically, with some individuals experiencing up to a fourfold faster progression compared to others. This variability stems from genes involved in DNA repair, though the same variants can stabilize some repeats while destabilizing others.
Notably, the study pinpointed a new association: expansions in the GLS gene, present in about 0.03% of people, correlate with a 14-fold higher risk of severe kidney disease and a three-fold increase in liver disease risk. Expanded repeats are known to underlie more than 60 inherited disorders, such as Huntington's disease, myotonic dystrophy, and certain forms of ALS, by disrupting normal cell function.
"We found that most human genomes contain repeat elements that expand as we age," said Margaux L. A. Hujoel, PhD, lead author and assistant professor at UCLA's David Geffen School of Medicine. "The strong genetic control of this expansion, with some individuals' repeats expanding four times faster than others, points to opportunities for therapeutic intervention."
These insights suggest that tracking repeat expansions in blood could serve as a biomarker for evaluating treatments in repeat-expansion diseases. The tools and data may uncover more hidden links to illnesses in other biobanks, though further research is needed to explain differing effects across cell types.
