Combining cross-sectional and longitudinal genomic approaches to identify determinants of cognitive and physical decline

Tabea Schoeler (), Jean-Baptiste Pingault and Zoltán Kutalik ()
Additional contact information
Tabea Schoeler: University of Lausanne
Jean-Baptiste Pingault: University College London
Zoltán Kutalik: University of Lausanne

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Large-scale genomic studies focusing on the genetic contribution to human aging have mostly relied on cross-sectional data. With the release of longitudinally curated aging phenotypes by the UK Biobank (UKBB), it is now possible to study aging over time at genome-wide scale. In this work, we evaluated the suitability of competing models of change in realistic simulation settings, performed genome-wide association scans on simulation-validated measures of age-related deweekcline, and followed up with LD-score regression and Mendelian Randomization (MR) analyses. Focusing on global cognitive and physical function, we observed marked differences between baseline function (θ) and accelerated decline (Δ). Both outcomes showed distinct heritability levels (e.g., 31.38% $${h}_{\theta }^{2}$$ h θ 2 versus 3.15% $${h}_{\Delta }^{2}$$ h Δ 2 for physical function) and different associated loci (e.g., DUSP6 specific to physical Δ). Further, we found little commonalities across the two dimensions of aging—while cognitive decline was largely driven by Alzheimer’s disease liability (standardized MR-effect, γ = 0.17), physical decline was mostly impacted by telomere length (γ = −0.05) and bone mineral density (γ = −0.05). Our work highlights the utility of longitudinal genomic efforts to scrutinize age-dependent genetic and environmental effects on physical and cognitive outcomes. Careful modelling and attention to participation characteristics are, however, crucial for valid inference.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59383-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59383-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59383-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().