Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan,Nature Medicine

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Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan
Nature Medicine ( IF 82.9 ) Pub Date : 2020-03-23 , DOI: 10.1038/s41591-020-0785-8
Saori Sakaue _{1,

2,

3} , Masahiro Kanai _{1,

2,

4,

5,

6,

7,

8} , Juha Karjalainen _{4,

5,

6,

8} , Masato Akiyama _{1,

9} , Mitja Kurki _{4,

5,

6,

8} , Nana Matoba ₁ , Atsushi Takahashi _{1,

10} , Makoto Hirata ₁₁ , Michiaki Kubo ₁₂ , Koichi Matsuda ₁₃ , Yoshinori Murakami ₁₄ , , Mark J Daly _{4,

5,

6,

8} , Yoichiro Kamatani _{1,

15} , Yukinori Okada _{2,

16,

17}

Affiliation

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Japan.
Laboratory of Genome Technology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Division of Molecular Pathology, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.
Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks¹, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted². To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (n_total = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02–1.04], P_meta = 3.9 × 10⁻¹³) and parental lifespan (hazard ratio = 1.06[1.06–1.07], P = 2.0 × 10⁻⁸⁶). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (P_{heterogeneity} = 9.5 × 10⁻⁸ for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype–phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.

中文翻译：

对 676,000 人的跨生物库分析阐明了复杂性状的多基因风险评分与人类寿命的关联

虽然多基因风险评分 (PRS) 有望通过预测先天健康风险¹转化为临床实践，但有必要采用一种利用遗传学来优先考虑驱动健康结果的可改变风险因素的策略²。为此，我们与三个全球生物库（n_总数 = 675,898；日本生物库（n = 179,066）、英国生物库（n = 361,194）和 FinnGen（n = 135,638))。与难以辨别因果关系的观察性研究相比，PRS 可以帮助识别影响人类寿命的驱动生物标志物。高收缩压 PRS 与较短的寿命（风险比 = 1.03[1.02–1.04]，P _meta = 3.9 × 10 ^-13）和父母的寿命（风险比 = 1.06[1.06–1.07]，P = 2.0 × 10 ^-86 )。肥胖 PRS 对日本和欧洲个体的寿命有明显影响 ( P_异质性 = 9.5 × 10 ^-8BMI）。孟德尔随机化研究进一步支持了血压和肥胖对寿命的因果影响。除了基因型-表型关联之外，我们的跨生物样本库研究提供了 PRS 在优先考虑风险因素方面的新价值，这些风险因素可能成为改善人口健康的潜在药物治疗目标。

更新日期：2020-03-23

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