Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37550455.
- Also identified by DOI 10.1038/s43587-023-00455-5 and PMC identifier 10432278.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10<sup>-5</sup>). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10<sup>-10</sup>), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10<sup>-6</sup>), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.
Medical subject headings
- Genome-Wide Association Study
- Healthy Aging