Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Neurobiol Aging. 2022 Dec;120:128-136. doi: 10.1016/j.neurobiolaging.2022.09.002. Epub 2022 Sep 10.
The related genetic variants of tau deposition, a seminal pathological hallmark of Alzheimer's disease, remain poorly understood. We sought to perform a genome-wide association study of brain tau load as measured by AV1451 positron emission tomography (PET). Among 543 non-demented European individuals, novel associations with higher tau were identified for rs56298435 (p = 8.35 × 10, β=0.31) within ZBTB20, and for rs150532 (p = 1.90 × 10, β=0.26) in the protein phosphorylation regulatory gene EYA4. The APOE association additionally reached genome-wide significant when APOE ε4 was not adjusted. Minor allele carriers of rs56298435 or rs150532 showed higher levels of tau PET load. As expected, phosphorylated-tau analyses in both plasma and cerebrospinal fluid also revealed the same direction of effect. Functionally, the effects of novel loci on cognitive decline could be mediated by tau pathology. In addition, we observed that the expression of VNN2 as regulated by rs150532, together with EYA4, displayed significant correlations with the tau-related gene MAPT in numerous brain regions. Our novel finding lends additional credence to heritable underpinnings of tau deposition.
tau 沉积的相关遗传变异是阿尔茨海默病的一个重要病理学标志，但目前仍了解甚少。我们试图通过 AV1451 正电子发射断层扫描（PET）测量脑 tau 负荷进行全基因组关联研究。在 543 名非痴呆的欧洲个体中，我们发现了与 ZBTB20 内 rs56298435（p = 8.35×10，β=0.31）和蛋白磷酸化调节基因 EYA4 内 rs150532（p = 1.90×10，β=0.26）更高 tau 值相关的新关联。当不调整 APOE ε4 时，APOE 关联也达到了全基因组显著水平。rs56298435 或 rs150532 的 minor 等位基因携带者 tau PET 负荷更高。正如预期的那样，在血浆和脑脊液中的磷酸化 tau 分析也显示出相同的效果。从功能上讲，新发现的基因座对认知能力下降的影响可能是由 tau 病理学介导的。此外，我们观察到 rs150532 调节的 VNN2 与 EYA4 的表达与多个脑区的 tau 相关基因 MAPT 呈显著相关。我们的新发现进一步证实了 tau 沉积的遗传性基础。
