Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
Statistical Consulting Unit StaBLab, Department of Statistics, LMU Munich, Munich, Germany.
Nat Commun. 2024 Nov 20;15(1):10061. doi: 10.1038/s41467-024-54483-9.
Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use seven statistical approaches to analyze the UK Biobank data and simulated data, finding that a linear mixed model is a powerful approach with unbiased effect estimates which is viable for longGWAS. The linear mixed model identifies 13 independent genetic variants associated with eGFR-decline, including 6 novel variants, and links them to age-dependent eGFR-genetics. We demonstrate that age-dependent and age-independent eGFR-genetics exhibit a differential pattern regarding clinical progression traits and kidney-specific gene expression regulation. Overall, our results provide insights into kidney aging and linear mixed model-based longGWAS generally.
了解肾功能下降的遗传学，或一般特征变化的遗传学，受到用于 GWAS（长 GWAS）的纵向数据稀缺和不确定如何分析此类数据的阻碍。我们使用来自 348275 个人的基于肌酐的估算肾小球滤过率的 UK Biobank 纵向数据，来搜索与 eGFR 下降相关的遗传变异。该搜索是在以前与横断面 GWAS 和全基因组关联的与 eGFR 相关的 595 个变异中进行的。我们使用七种统计方法来分析 UK Biobank 数据和模拟数据，发现线性混合模型是一种强大的方法，具有无偏的效应估计值，对于长 GWAS 是可行的。线性混合模型确定了与 eGFR 下降相关的 13 个独立遗传变异，包括 6 个新的变异，并将它们与依赖年龄的 eGFR 遗传学联系起来。我们证明，依赖年龄和不依赖年龄的 eGFR 遗传学在临床进展特征和肾脏特异性基因表达调控方面表现出不同的模式。总体而言，我们的结果提供了对肾脏衰老和基于线性混合模型的长 GWAS 的深入了解。
