Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan
Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan
Abstract Human genetics seeks a way to improve human health on a global scale. Expectations are running high for polygenic risk scores (PRSs) to be translated into clinical practice to predict an inborn susceptibility to health risks. While risk stratification based on PRS is one way to promote population health, a strategy to utilize genetics to prioritize modifiable risk factors and biomarkers driving heath outcome is also warranted. To this end, here we utilized PRSs to comprehensively investigate the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898). First, we conducted genome-wide association studies for 45 quantitative clinical phenotypes, constructed the individual PRSs, and associated them with the age at death of 179,066 participants in BioBank Japan. The PRSs revealed that the genetic susceptibility of high systolic blood pressure (sBP) was strongly associated with a shorter lifespan (hazard ratio [HR] = 1.03, P = 1.4×10-7). Next, we sought to replicate these associations in individuals of European ancestry in UK Biobank (n = 361,194) and FinnGen (n = 135,638). Among the investigated traits, the individuals with higher blood pressure-related PRSs were trans-ethnically associated with a shorter lifespan (HR = 1.03, Pmeta = 3.9×10-13 for sBP) and parental lifespan (HR = 1.06, PUKBB = 2.0×10-86 for sBP). Further, our trans-biobank study identified additional complex traits associated with lifespan (e.g., obesity, height, serum lipids, and platelet counts). Of them, obesity-related traits showed strikingly heterogeneous effects on lifespan between Japanese and European populations (Pheterogeneity = 9.5×10-8 for body mass index). Through trans-ethnic biobank collaboration, we elucidated the novel value of the PRS study in genetics-driven prioritization of risk factors and biomarkers which can be medically intervened to improve population health.
Kurki Mitja、Sakaue Saori、Karjalainen Juha、Hirata Makoto、Matsuda Koichi、FinnGen、Akiyama Masato、Okada Yukinori、Daly Mark J.、Murakami Yoshinori、Takahashi Atsushi、Kanai Masahiro、Kubo Michiaki、Matoba Nana、Kamatani Yoichiro
Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Institute for Molecular Medicine Finland (FIMM), University of HelsinkiLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences||Department of Statistical Genetics, Osaka University Graduate School of Medicine||Department of Allergy and Rheumatology, Graduate School of Medicine, the University of TokyoAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Institute for Molecular Medicine Finland (FIMM), University of HelsinkiLaboratory of Genome Technology, Institute of Medical Science, the University of TokyoDepartment of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, the University of TokyoLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences||Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Statistical Genetics, Osaka University Graduate School of Medicine||Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University||Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka UniversityAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Institute for Molecular Medicine Finland (FIMM), University of HelsinkiDivision of Molecular Pathology, the Institute of Medical Sciences, the University of TokyoLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences||Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular CenterLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences||Department of Statistical Genetics, Osaka University Graduate School of Medicine||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Department of Biomedical Informatics, Harvard Medical School||Institute for Molecular Medicine Finland (FIMM), University of HelsinkiRIKEN Center for Integrative Medical SciencesLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical SciencesLaboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences||Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo
医学研究方法遗传学生物科学研究方法、生物科学研究技术
Kurki Mitja,Sakaue Saori,Karjalainen Juha,Hirata Makoto,Matsuda Koichi,FinnGen,Akiyama Masato,Okada Yukinori,Daly Mark J.,Murakami Yoshinori,Takahashi Atsushi,Kanai Masahiro,Kubo Michiaki,Matoba Nana,Kamatani Yoichiro.Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/856351.点此复制
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