Parkinson Disease: Predicting the Future

帕金森氏病：预测未来 人们对帕金森氏症患者的病程有侵袭性的原因知之甚少。发展的步伐 进展差异很大，从可控的功能下降到加速的进程 让患者迅速地被轮椅绑住或患有痴呆症。这是患者痛苦的来源， 照顾者。在临床试验中，这种变异混淆了药物效果。许多基因变异被认为与 易感性，但调控疾病进展的基因还没有得到很好的确定。我们的初步研究 表示多种编码和非编码变体，预示着超速运动或记忆力下降。 我们假设，基因变异将有力地预测帕金森氏症的进展。 通过对10个队列进行高覆盖率、大规模并行、有针对性的排序，直接解决这个问题 来自北美和欧洲，其纵向特征是在 课程长达12年。3939例帕金森病患者和3万多名临床患者 评估将使用考克斯模型和混合随机和固定效应模型进行分析。在目标1中，我们将确定 预测认知或运动进展的易感基因和家族性基因的遗传变异。 此外，我们还将评估从外显子组规模搜索中出现的新的可能进展的基因座。在目标2中， 我们将在独立的种群中复制和验证转发的遗传变异。 这项研究将建立帕金森氏病的第一个进展基因，阐明预后和转变 我们设计临床试验的方式。破坏蛋白质功能的罕见变异将会告知潜在的 机制并为治疗提供线索。更广泛地说，这些数据将有助于提高精度 医学将改变医疗保健。

Parkinson’s Disease: Predicting the Future It is poorly understood why some patients with Parkinson’s have an aggressive disease course. The pace of progression varies considerably, ranging from a manageable functional decline to an accelerated course that leaves patients rapidly wheelchair bound or with dementia. This is a source of anguish for patients and caregivers. In clinical trials, this variation obfuscates drug effects. Many genetic variants have been linked to susceptibility, but the genes modulating disease progression have not been well established. Our initial studies indicate multiple coding and noncoding variants predictive of a hyper-accelerated motor or memory decline. We hypothesize that genetic variants will powerfully predict the progression of Parkinson’s. We will directly address this question through high coverage, massively parallel, targeted sequencing of ten cohorts from North America and Europe that were longitudinal characterized with exceptional granularity over the course of up to twelve years. 3,939 patients with Parkinson’s disease and over thirty thousand clinical assessments will be analyzed using Cox and mixed random and fixed effect models. In Aim 1, we will identify genetic variants in susceptibility loci and familial genes that predict cognitive or motor progression. Furthermore, novel putative progression loci emerging from our exome-scale search will be evaluated. In Aim 2, we will replicate and verify forwarded genetic variants in independent populations. This study will establish the first progression genes for Parkinson’s disease, clarify prognosis, and shift the way we design clinical trials. Rare variants that disrupt protein function will inform on the underlying mechanism and reveal clues for therapies. More generally, these data will contribute towards a precision medicine poised to transform healthcare.