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

Paul R.H.J. Timmers, Evgeny S. Tiys, Saori Sakaue, Masato Akiyama, Tuomo T.J. Kiiskinen, Wei Zhou, Shih Jen Hwang, Chen Yao, Yoichiro Kamatani, Wei Zhou, Joris Deelen, Daniel Levy, Andrea Ganna, Yoichiro Kamatani, Yukinori Okada, Peter K. Joshi, James F. Wilson, Yakov A. Tsepilov

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)19-30
Number of pages12
JournalNature Aging
Volume2
Issue number1
DOIs
Publication statusPublished - Jan 2022

OECD FOS+WOS

  • 3.02.LJ GERONTOLOGY
  • 3.02.LI GERIATRICS & GERONTOLOGY

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