Schoeler Tabea, Pingault Jean-Baptiste, Kutalik Zoltán
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Department of Clinical, Educational and Health Psychology, University College London, London, UK.
Nat Commun. 2025 May 15;16(1):4524. doi: 10.1038/s41467-025-59383-0.
Large-scale genomic studies focusing on the genetic contribution to human aging have mostly relied on cross-sectional data. With the release of longitudinally curated aging phenotypes by the UK Biobank (UKBB), it is now possible to study aging over time at genome-wide scale. In this work, we evaluated the suitability of competing models of change in realistic simulation settings, performed genome-wide association scans on simulation-validated measures of age-related deweekcline, and followed up with LD-score regression and Mendelian Randomization (MR) analyses. Focusing on global cognitive and physical function, we observed marked differences between baseline function (θ) and accelerated decline (Δ). Both outcomes showed distinct heritability levels (e.g., 31.38% versus 3.15% for physical function) and different associated loci (e.g., DUSP6 specific to physical Δ). Further, we found little commonalities across the two dimensions of aging-while cognitive decline was largely driven by Alzheimer's disease liability (standardized MR-effect, γ = 0.17), physical decline was mostly impacted by telomere length (γ = -0.05) and bone mineral density (γ = -0.05). Our work highlights the utility of longitudinal genomic efforts to scrutinize age-dependent genetic and environmental effects on physical and cognitive outcomes. Careful modelling and attention to participation characteristics are, however, crucial for valid inference.
专注于人类衰老遗传贡献的大规模基因组研究大多依赖于横断面数据。随着英国生物银行（UKBB）纵向整理的衰老表型数据的发布，现在有可能在全基因组范围内研究随时间变化的衰老情况。在这项工作中，我们评估了竞争变化模型在现实模拟环境中的适用性，对经模拟验证的与年龄相关衰退的测量指标进行了全基因组关联扫描，并随后进行了连锁不平衡评分回归和孟德尔随机化（MR）分析。聚焦于整体认知和身体功能，我们观察到基线功能（θ）和加速衰退（Δ）之间存在显著差异。这两个结果都显示出不同的遗传力水平（例如，身体功能的遗传力分别为31.38%和3.15%）以及不同的相关基因座（例如，特定于身体Δ的DUSP6）。此外，我们发现衰老的两个维度之间几乎没有共性——认知衰退在很大程度上由阿尔茨海默病易感性驱动（标准化MR效应，γ = 0.17），而身体衰退主要受端粒长度（γ = -0.05）和骨矿物质密度（γ = -0.05）的影响。我们的工作突出了纵向基因组研究在审视年龄依赖性遗传和环境对身体及认知结果影响方面的作用。然而，仔细建模和关注参与特征对于有效推断至关重要。
