Gaudio Andrea, Gotta Fabio, Ponti Clarissa, Geroldi Alessandro, La Barbera Andrea, Mandich Paola
IRCCS Ospedale Policlinico San Martino-UOC Genetica Medica, Largo R. Benzi 10, 16132 Genova, Italy.
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genova, Largo P. Daneo 3, 16132 Genova, Italy.
Int J Mol Sci. 2025 Apr 10;26(8):3578. doi: 10.3390/ijms26083578.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia and abnormal behaviors occurring during REM sleep. Idiopathic RBD (iRBD) is recognized as the strongest prodromal hallmark of α-synucleinopathies, with an established conversion rate to a neurodegenerative condition that reaches up to 96.6% at 15 years of follow-up. Moreover, RBD-converters display a more severe clinical trajectory compared to those that do not present with RBD. However, the extent to which iRBD represents a distinct genetic entity or an early manifestation of neurodegeneration remains unclear. To address this, we applied Genomic Structural Equation Modeling (GenomicSEM) using a GWAS-by-subtraction approach to disentangle the genetic architecture of iRBD from the shared genomic liability across α-synucleinopathies. Our findings highlight the locus as a key genetic regulator of iRBD susceptibility. While iRBD exhibits a partially distinct genetic signature, residual genomic overlap with neurodegenerative traits suggests that its genetic architecture exists along a continuum of α-synucleinopathy risk. In this scenario, the associations with neuroanatomical correlates may serve as early indicators of a trajectory toward future neurodegeneration. These findings provide a framework for identifying biomarkers that could aid in disease stratification and risk prediction, potentially improving early intervention strategies.
快速眼动（REM）睡眠行为障碍（RBD）是一种异态睡眠，其特征是在REM睡眠期间肌肉张力缺失和出现异常行为。特发性RBD（iRBD）被认为是α-突触核蛋白病最强的前驱标志，在15年的随访中，其发展为神经退行性疾病的转化率高达96.6%。此外，与未出现RBD的患者相比，RBD转化者表现出更严重的临床病程。然而，iRBD在多大程度上代表一个独特的遗传实体或神经退行性变的早期表现仍不清楚。为了解决这个问题，我们应用基因组结构方程模型（GenomicSEM），采用减法全基因组关联研究（GWAS）方法，将iRBD的遗传结构与α-突触核蛋白病共有的基因组易感性区分开来。我们的研究结果突出了该基因座是iRBD易感性的关键遗传调节因子。虽然iRBD表现出部分独特的遗传特征，但与神经退行性特征的残余基因组重叠表明，其遗传结构存在于α-突触核蛋白病风险的连续统一体中。在这种情况下，与神经解剖学相关性的关联可能作为未来神经退行性变轨迹的早期指标。这些发现为识别有助于疾病分层和风险预测的生物标志物提供了一个框架，可能改善早期干预策略。
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