Publication
Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging
Publisher:
Springer Science and Business Media LLC
Date:
07-08-2023
DOI:
10.1038/S43587-023-00455-5
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 in idually. 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 −5 ). Similarly, genetically proxied thiazolidinediones ( P value = 3.50 × 10 −10 ), proprotein convertase subtilisin/kexin 9 inhibition ( P value = 1.62 × 10 −6 ), 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.