Mendelian randomization of genetically independent aging phenotypes identifies 
LPA and VCAM1 as biological targets for human aging

Timmers, P. R. H. J.; Tiys, E. S.; Sakaue, S.; Akiyama, M.; Kiiskinen, T. T. J.; Zhou, W.; Hwang, S.-J.; Yao, C.; Kamatani, Y.; Zhou, W.; Deelen, J.; Levy, D.; Ganna, A.; Kamatani, Y.; Okada, Y.; Joshi, P. K.; Wilson, J. F.; Tsepilov, Y. A.

doi:10.1038/s43587-021-00159-8

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Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging

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Deelen, J.
Deelen – Genetics and Biomarkers of Human Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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https://doi.org/10.1038/s43587-021-00159-8
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Timmers, P. R. H. J., Tiys, E. S., Sakaue, S., Akiyama, M., Kiiskinen, T. T. J., Zhou, W., et al. (2022). Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging. Nature Aging, 2(1), 19-30. doi:10.1038/s43587-021-00159-8.

Cite as: https://hdl.handle.net/21.11116/0000-000B-B68F-7

Abstract

Length and quality of life are important to us all, yet identification of promising drug targets for human aging using genetics has had limited success. In the present study, we combine six European-ancestry genome-wide association studies of human aging traits—healthspan, father and mother lifespan, exceptional longevity, frailty index and self-rated health—in a principal component framework that maximizes their shared genetic architecture. The first principal component (aging-GIP1) captures both length of life and indices of mental and physical wellbeing. We identify 27 genomic regions associated with aging-GIP1, and provide additional, independent evidence for an effect on human aging for loci near HTT and MAML3 using a study of Finnish and Japanese survival. Using proteome-wide, two-sample, Mendelian randomization and colocalization, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) and vascular cell adhesion molecule 1 on aging-GIP1. Together, our results demonstrate that combining multiple aging traits using genetic principal components enhances the power to detect biological targets for human aging.