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<p>Aging is accompanied by widespread DNA methylation changes, yet their full genomic scope and parent-of-origin dynamics remain poorly understood. Here, we apply nanopore long-read sequencing to 7,284 whole blood samples enabling methylation measurements of 17,959,684 high-quality CpG units. Over 20% of the measured high quality CpG&#xa0;units undergo age-associated changes, predominantly hypomethylation. From these data, we construct a methylation aging clock from 1,373 high-quality CpG&#xa0;units, with median absolute prediction error of 2.43 years. Importantly, phasing the methylation to parental haplotypes enables systematic analysis of age effects in parent-of-origin specific context, uncovering 702 high-quality CpG&#xa0;units with parent-of-origin specific age-association, most of which are located at imprinted genomic regions. At the <i>DIRAS3</i> locus, we detect age-dependent hypermethylation on the active paternal allele, indicative of attenuation of parent-of-origin specific methylation with age. Together, these findings establish nanopore sequencing as a powerful tool for mapping both genome-wide and parent-of-origin specific signatures of methylation aging and provide evidence that methylation patterns at imprinted loci become progressively altered with age.</p>

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Nanopore sequencing identifies parent-of-origin specific age-associated methylation changes at imprinted loci in the human genome

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月29日

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  • Brynja Sigurpalsdottir,
  • Guillaume Holley,
  • Sverrir Þ. Sverrisson,
  • Droplaug N. Magnusdottir,
  • Pall I. Olafsson,
  • Arnaldur Gylfason,
  • Olafur Þ. Magnusson,
  • Gisli Masson,
  • Olafur A. Stefansson,
  • Bjarni V. Halldorsson

摘要

Aging is accompanied by widespread DNA methylation changes, yet their full genomic scope and parent-of-origin dynamics remain poorly understood. Here, we apply nanopore long-read sequencing to 7,284 whole blood samples enabling methylation measurements of 17,959,684 high-quality CpG units. Over 20% of the measured high quality CpG units undergo age-associated changes, predominantly hypomethylation. From these data, we construct a methylation aging clock from 1,373 high-quality CpG units, with median absolute prediction error of 2.43 years. Importantly, phasing the methylation to parental haplotypes enables systematic analysis of age effects in parent-of-origin specific context, uncovering 702 high-quality CpG units with parent-of-origin specific age-association, most of which are located at imprinted genomic regions. At the DIRAS3 locus, we detect age-dependent hypermethylation on the active paternal allele, indicative of attenuation of parent-of-origin specific methylation with age. Together, these findings establish nanopore sequencing as a powerful tool for mapping both genome-wide and parent-of-origin specific signatures of methylation aging and provide evidence that methylation patterns at imprinted loci become progressively altered with age.