The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and healthspan. Here, we leveraged summary statistics of a genome-wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype-Tissue Expression project through a combination of multi-tissue transcriptome-wide association analyses and genetic colocalization. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan that may offer new drug repositioning opportunities for healthspan such as drugs targeting apolipoprotein-B-containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome-wide MR analyses were used to map genetically regulated genes, proteins and metabolites with the disease-related phenome in the UK Biobank and FinnGen. Altogether, this study identified novel biological determinants of aging and potential therapeutic targets for human healthspan extension.

中文翻译：

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父母寿命跨学科的孟德尔式跨随机研究发现了人类健康扩展的新型衰老生物学和候选药物

对父母寿命的研究已成为一种创新工具，可以促进衰老生物学以及我们对人类寿命和健康寿命遗传结构的理解。在这里，我们利用多组织转录组范围内的关联分析与遗传共定位相结合的方法，利用包括超过一百万个父母寿命在内的全基因组范围内关联研究的摘要统计信息，从基因型组织表达项目中识别出基因调控的基因。孟德尔随机（MR）分析还确定了与父母寿命有因果关系的循环蛋白和代谢产物，这些代谢产物可能为健康期提供新的药物重新定位机会，例如靶向载脂蛋白B的脂蛋白药物。编码触珠蛋白的基因HP的肝脏表达 血浆触珠蛋白水平与父母的寿命有因果关系。在英国生物库和FinnGen中，对全基因组的MR分析用于绘制与疾病相关的表型的基因调控基因，蛋白质和代谢产物。总而言之，这项研究确定了衰老的新生物学决定因素和人类健康扩展的潜在治疗靶标。