NEW YORK – A new study into the genetics of telomere length has highlighted rare variants and genes previously implicated in clonal hematopoiesis.
"We show the substantial impact of rare variants as well as the significant effects of genes related to clonal hematopoiesis," Slavé Petrovski, corresponding author of a study published in Nature Genetics on Tuesday and VP of the AstraZeneca Centre for Genomics Research, said in an email. "This marks a significant advancement in connecting telomere biology with age-related somatic changes and diseases — a link not explicitly established in prior research."
Using whole-genome sequence data for 490,397 UK Biobank participants, the researchers first came up with a method for estimating telomere length based on a combination of in silico analyses of the genome with the TelSeq tool and telomere sequence-focused quantitative PCR measurements (qPCR) — an approach that appeared to yield more accurate telomere lengths than either method alone.
"By leveraging half a million genome sequences from the UK Biobank with paired qPCR data, our study introduces an innovative, integrated telomere length metric that enhances our understanding of telomere biology and could potentially lead to more personalized strategies in managing aging and associated disorders," Petrovski explained.
"The introduction of this enhanced telomere length metric holds promise to refine predictive models for aging and longevity," he added. "It is an exciting step forward, suggesting that a deeper understanding of telomere dynamics could significantly influence future therapeutic developments."
The team then used the telomere length metric — in combination with genome sequence or array-based genotyping data for the UK Biobank participants — to search for rare and common genetic variants contributing to telomere length variation.
On the common variant side, the GWAS led to 192 telomere length-associated loci, including more than 100 found in a 2021 study published in Nature Genetics that involved nearly 472,200 UK Biobank participants assessed with qPCR-based telomere measurements.
The researchers also highlighted 62 rare variants falling in 19 distinct genes, including 39 variants with ties to longer-than-usual telomeres and 23 rare, non-synonymous variants linked to abbreviated telomeres. By bringing in gene-level analyses, meanwhile, they saw 64 telomere length-associated protein-coding variants involving 30 genes.
In particular, the findings pointed to the importance of genes contributing to clonal hematopoiesis — age-related somatic mosaicism in blood that has been linked to increased risk of myeloid cancer types and other conditions outside of the hematological system.
Together, the results "support a key role for telomere maintenance in the development of [clonal hematopoiesis], via mechanisms specific to the mutant gene driving clonal expansion," the authors wrote, adding that "therapeutic modulation of telomere biology might be an important focus as strategies for prevention and treatment of [clonal hematopoiesis] and its sequelae."