Yang Wenzhi, Xiao Wendi, Liu Xiangyi, Li Hui, Huang Tao, Fan Dongsheng
Department of Neurology, Peking University Third Hospital, Beijing 100080, China.
Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100080, China.
Biomedicines. 2025 Mar 4;13(3):622. doi: 10.3390/biomedicines13030622.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease characterized by the degeneration of spinal cord and brain neurons. Proteomics combined with Mendelian randomization (MR) is an effective method for finding disease treatment targets. We aimed to seek new therapeutic targets for ALS. A large-scale GWAS on proteomics (4907 circulatory protein) with 35,559 individuals was included as the exposure data; a GWAS with 138,086 ALS patients was used as the outcome data; we found that a high level of sex hormone-binding globulin (SHBG) is a risk factor by MR analysis. Colocalization analyses were used to validate the causality between SHBG and ALS further. Functional enrichment found a high level of SHBG was associated with a low level of bioavailable testosterone. Two-sample MR confirmed the association of SHBG (400,210 samples), bioavailable testosterone (367,289 samples), and ALS. : A high level of SHBG, and a low level of bioavailable testosterone are risk factors for ALS. A low level of bioavailable testosterone is a risk factor for ALS. Although our study is relatively limited and cannot fully confirm that testosterone supplementation has a therapeutic effect on ALS, it offers a promising direction for ALS therapy.
肌萎缩侧索硬化症（ALS）是一种进行性致命疾病，其特征是脊髓和脑神经元退化。蛋白质组学与孟德尔随机化（MR）相结合是寻找疾病治疗靶点的有效方法。我们旨在寻找ALS的新治疗靶点。纳入一项对35559名个体进行的大规模蛋白质组学全基因组关联研究（GWAS）（4907种循环蛋白）作为暴露数据；将一项对138086例ALS患者进行的GWAS用作结局数据；通过MR分析我们发现高水平的性激素结合球蛋白（SHBG）是一个风险因素。共定位分析用于进一步验证SHBG与ALS之间的因果关系。功能富集发现高水平的SHBG与低水平的生物可利用睾酮有关。两样本MR证实了SHBG（400210个样本）、生物可利用睾酮（367289个样本）与ALS之间的关联。高水平的SHBG和低水平的生物可利用睾酮是ALS的风险因素。低水平的生物可利用睾酮是ALS的风险因素。尽管我们的研究相对有限，不能完全证实补充睾酮对ALS有治疗作用，但它为ALS治疗提供了一个有前景的方向。
