Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.
Department of Neurology, Harvard Medical School, Boston, MA, USA.
Mol Psychiatry. 2018 Jun;23(6):1521-1529. doi: 10.1038/mp.2017.20. Epub 2017 Mar 21.
Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid β plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid β plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.
tau 病包括阿尔茨海默病 (AD) 和其他神经退行性疾病，其特征为存在神经纤维缠结 (NFT)。NFT 的积累被认为与 AD 中的认知能力下降密切相关。在这里，我们对 NFT 病理负担进行了全基因组关联研究，并在 909 例前瞻性尸检中报告了 PTPRD 基因座(rs560380，P=3.8×10)的关联。该关联在 369 例独立尸检数据集中得到了复制。PTPRD 与 NFT 的关联与淀粉样蛋白病理学的积累无关。相比之下，我们发现 ZCWPW1 AD 易感性变异影响 NFT 的积累，并且这种影响是通过淀粉样 β 斑块的积累介导的。我们还进行了补充分析，以确定影响与 NFT 共存的多种神经病理学的共同途径，并发现了一些暗示性证据，表明某些基因座可能影响多种不同的神经病理学特征，包括 tau、淀粉样 β 斑块、血管损伤和路易体。总体而言，这些分析评估了对 NFT 的遗传易感性，NFT 是多种不同病理过程的共同终点。
