Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Precision Neurology Program of Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Genet. 2021 Jun;53(6):787-793. doi: 10.1038/s41588-021-00847-6. Epub 2021 May 6.
A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10) and WWOX (HR = 2.12, P = 2.37 × 10) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
患者的健康状况和帕金森病 (PD) 的临床试验的一个关键驱动因素是疾病随时间的发展过程（进展和预后）。为了评估遗传变异如何影响 PD 向痴呆症的时间进展，这是生活质量的主要决定因素，我们对 3821 名 PD 患者的 1120 万个变体进行了长达 31053 次随访的纵向全基因组生存研究。我们发现 RIMS2 是一个进展基因座，并在复制人群中得到了证实（风险比 (HR) = 4.77，P = 2.78 × 10），对 TMEM108（HR = 2.86，P = 2.09 × 10）和 WWOX（HR = 2.12，P = 2.37 × 10）也有提示性证据表明是进展基因座，并证实了 GBA（HR = 1.93，P = 0.0002）和 APOE（HR = 1.48，P = 0.001）的关联。多基因进展评分与痴呆风险有很大的综合关联，而多基因易感性评分没有预测能力。这项研究确定了 PD 中认知疾病进展的一个新的突触基因座和多基因评分，并提出了进展和易感性的不同遗传结构。
