TY - JOUR

T1 - Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging

AU - Timmers, Paul R.H.J.

AU - Tiys, Evgeny S.

AU - Sakaue, Saori

AU - Akiyama, Masato

AU - Kiiskinen, Tuomo T.J.

AU - Zhou, Wei

AU - Hwang, Shih Jen

AU - Yao, Chen

AU - Kamatani, Yoichiro

AU - Zhou, Wei

AU - Deelen, Joris

AU - Levy, Daniel

AU - Ganna, Andrea

AU - Kamatani, Yoichiro

AU - Okada, Yukinori

AU - Joshi, Peter K.

AU - Wilson, James F.

AU - Tsepilov, Yakov A.

N1 - Funding Information: We thank the UK Biobank Resource, approved under application 19655. We thank the Medical Research Council Human Genetics Unit for their funding (to P.R.H.J.T. and J.F.W.: grant no. MC_UU_00007/10), and also the University of Edinburgh (to P.K.J.), the Russian Ministry of Education and Science 5-100 Excellence Programme (to E.S.T. and Y.A.T.) and the Ministry of Education and Science of the RF via the Institute of Cytology and Genetics SB RAS (to E.S.T. and Y.A.T.: grant no. 0259-2021-0009/AAAA-A17-117092070032-4). The FinnGen project and authors (T.T.J.K., W.Z. and A.G.) acknowledge funding from Business Finland (nos. HUS 4685/31/2016 and UH 4386/31/2016) as well as the industry partners AbbVie Inc., AstraZeneca UK Ltd., Biogen MA Inc., Celgene Corporation, Celgene International II Sàrl, Genentech Inc., Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc. and Novartis AG. The following biobanks are acknowledged for their samples in the FinnGen project: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi) and FinBB (https://finbb.fi). The Framingham Heart Study is funded by a National Institutes of Health (NIH) contract (nos. N01-HC-25195, HHSN268201500001I and 75N92019D00031; Boston University). This project was funded in part by the Division of Intramural Research, National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, MD. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the NIH or the US Department of Health and Human Services. None of the funders had any role in study design, data collection and analysis, decision to publish or preparation of the manuscript. For the purpose of Open Access, the authors have applied a CC-BY public copyright license to any author accepted manuscript version arising from this submission. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

KW - Female

KW - Humans

KW - Genome-Wide Association Study/methods

KW - Mendelian Randomization Analysis

KW - Quality of Life

KW - Aging/genetics

KW - Phenotype

UR - http://www.scopus.com/inward/record.url?scp=85132304180&partnerID=8YFLogxK

U2 - 10.1038/s43587-021-00159-8

DO - 10.1038/s43587-021-00159-8

M3 - Article

C2 - 37118362

AN - SCOPUS:85132304180

VL - 2

SP - 19

EP - 30

JO - Nature Aging

JF - Nature Aging

SN - 2662-8465

IS - 1

ER -