Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Neuron. 2024 Jul 3;112(13):2142-2156.e5. doi: 10.1016/j.neuron.2024.04.002. Epub 2024 May 2.
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
多系统萎缩（MSA）是一种成人发病、散发性的突触核蛋白病，其特征为帕金森病、小脑共济失调和自主神经功能障碍。MSA 的遗传结构尚不清楚，治疗方法仅限于支持性措施。在这里，我们对 888 例欧洲血统 MSA 病例和 7128 例对照的全基因组序列数据进行了全面分析，以系统研究这种研究不足的神经退行性疾病的遗传基础。我们使用全基因组关联研究方法确定了四个显著相关的风险位点。转录组全关联分析将 USP38-DT、KCTD7 和 lnc-KCTD7-2 优先作为这些位点中 MSA 的新易感基因，单细胞 RNA 序列分析发现，相关变体在神经元和神经胶质细胞类型中作为多个基因的顺式表达数量性状基因座起作用。总之，这项研究强调了遗传决定因素在 MSA 发病机制中的作用，本研究中公开提供的数据代表了研究突触核蛋白病的宝贵资源。
