Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

帕金森病 (PD) 是一种使人衰弱的神经退行性疾病，其全球发病率不断上升，凸显了识别可改变危险因素的必要性。在对罕见变异（8647 个 PD 病例和 777,693 个对照）进行的基于基因的负担测试中，我们发现了ITSN1功能丧失变异与 PD 之间的新关联。该关联得到了神经退行性疾病知识门户和加速药物合作帕金森病知识平台的负担数据的进一步支持。我们的研究结果表明，Rho GTP 酶和突触小泡运输的破坏可能与 PD 的发病机制有关，这为新的治疗方法提供了可能性。