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; Biobank Japan Project; FinnGen; Joris Deelen; Daniel Levy; Andrea Ganna; Yoichiro Kamatani; Yukinori Okada; Peter K Joshi; James F Wilson; Yakov A Tsepilov

doi:10.1038/s43587-021-00159-8

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

Nat Aging. 2022 Jan;2(1):19-30. doi: 10.1038/s43587-021-00159-8. Epub 2022 Jan 20.

Authors

Paul R H J Timmers^{1

2}, Evgeny S Tiys^{3

4}, Saori Sakaue^{5

6

7

8}, Masato Akiyama^{9

10}, Tuomo T J Kiiskinen^{8

11}, Wei Zhou^{8

12

13}, Shih-Jen Hwang^{14

15}, Chen Yao^{14

15}; Biobank Japan Project; FinnGen; Joris Deelen^{16

17}, Daniel Levy^{14

15}, Andrea Ganna^{8

11

12}, Yoichiro Kamatani^{9

18}, Yukinori Okada⁶, Peter K Joshi¹⁹, James F Wilson^#^{20

19}, Yakov A Tsepilov^#^{3

21}

Collaborators

Yoichiro Kamatani, Wei Zhou

Affiliations

¹ MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. paul.timmers@ed.ac.uk.
² Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK. paul.timmers@ed.ac.uk.
³ Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, Russia.
⁴ Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk, Russia.
⁵ Center for Data Sciences, Harvard Medical School, Boston, MA, USA.
⁶ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
⁷ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁰ Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹¹ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
¹² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹³ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁴ Framingham Heart Study, Framingham, MA, USA.
¹⁵ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Max Planck Institute for Biology of Ageing, Cologne, Germany.
¹⁷ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
¹⁸ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
¹⁹ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
²⁰ MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
²¹ Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Novosibirsk, Russia.

^# Contributed equally.

PMID: 37118362
DOI: 10.1038/s43587-021-00159-8

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Female
Genome-Wide Association Study* / methods
Humans
Mendelian Randomization Analysis*
Phenotype
Quality of Life

Abstract

Publication types

MeSH terms

Grants and funding