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多变量全基因组分析与衰老相关的特征，确定了新的与健康衰老相关的基因座和新的药物靶点。

Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging.

机构信息

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

NIH-Oxford-Cambridge Scholars Program; Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

出版信息

Nat Aging. 2023 Aug;3(8):1020-1035. doi: 10.1038/s43587-023-00455-5. Epub 2023 Aug 7.

DOI:10.1038/s43587-023-00455-5
PMID:37550455
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10432278/
Abstract

The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.

摘要

衰老的概念很复杂，包括许多相关表型，如健康寿命、寿命、极端长寿、虚弱和表观遗传衰老，这表明它们具有共同的生物学基础；然而，与衰老相关的终点主要是单独评估的。我们使用来自这些特征和多变量全基因组关联研究方法的数据，对其潜在的遗传因素（“mvAge”）进行建模。mvAge（有效 n = ~190 万欧洲血统的参与者）在 38 个基因组位置中鉴定了 52 个独立的变体。其中 20 个变体是新的（未在输入的全基因组关联研究中报告）。转录组预测鉴定出与年龄相关的基因，包括 VEGFA 和 PHB1。用二甲双胍靶向基因进行药物-靶点孟德尔随机化研究表明，其对 mvAge 有有益的影响（P 值 = 8.41×10）。同样，与二甲双胍基因具有遗传相关性的噻唑烷二酮类药物（P 值 = 3.50×10）、脯肽酶枯草溶菌素/克酶素 9 抑制物（P 值 = 1.62×10）、血管生成素样蛋白 4、β受体阻滞剂和钙通道阻滞剂也具有有益的孟德尔随机化估计值。将药物-靶点孟德尔随机化框架扩展到 3947 个编码蛋白的基因中，优先考虑了 122 个靶点。这些发现将为未来旨在改善健康衰老的研究提供信息。

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