Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
Nat Commun. 2024 Sep 20;15(1):8251. doi: 10.1038/s41467-024-52298-2.
Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.
确定阿尔茨海默病病理的遗传结构可以增强对发病机制的理解，并为精准医疗策略提供信息。在这里，我们对来自 12 项独立研究的 3046 名参与者的皮质 Tau 通过正电子发射断层扫描进行了全基因组关联研究。CYP1B1-RMDN2 基因座与 Tau 沉积有关。最显著的信号位于 rs2113389，可解释皮质 Tau 变异的 4.3%，而 APOE4 rs429358 占 3.6%。rs2113389 与更高的 Tau 水平和更快的认知能力下降有关。在 rs2113389 与诊断、APOE4 和淀粉样蛋白β阳性之间观察到了累加效应，但没有相互作用。CYP1B1 的表达在 AD 中上调。rs2113389 与 CYP1B1 的更高表达和更高的甲基化水平有关。小鼠模型研究为 CYP1B1 与 Tau 沉积而不是淀粉样蛋白β之间的关系提供了额外的功能证据。这些结果深入了解了脑 Tau 沉积的遗传基础，并为 AD 的治疗开发提供了新的途径。
