Jia Tingting, Yang Fuhua, Qin Fengqin, He Yongji, Han Feng, Zhang Chengcheng
Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
CNS Neurosci Ther. 2025 Apr;31(4):e70370. doi: 10.1111/cns.70370.
Parkinson's disease (PD) and Lewy body dementia (LBD) have many common features, including clinical manifestations, neurochemistry, and pathology, but little is known about their shared brain proteins and genetic factors.
To identify susceptibility-related brain proteins that are shared between PD and LBD patients, proteome-wide association studies (PWASs) were conducted by integrating human brain protein quantitative trait loci (pQTLs) with large-scale genome-wide association studies (GWASs) of both diseases. Subsequently, pleiotropy-informed conditional false discovery rate (pleioFDR) analysis was performed to identify common risk genetic loci between PD and LBD. Finally, the downregulation of these risk genes in different disease states was validated by differential gene expression analysis.
PWASs identified 12 PD risk proteins and nine LBD risk proteins, among which TMEM175 (z = -7.25, P = 4.12E-13; z = -6.02, P = 1.75E-09) and DOC2A (z = -4.13, P = 3.71E-05; z = -3.91, P = 9.08E-05) were shared. PleioFDR analysis revealed that five genetic risk loci mapped to eight genes associated with PD and LBD, including the proteome-wide significant risk gene TMEM175 (ConjFDR = 5.74E-03). Differential expression analysis verified that TMEM175 was significantly downregulated in the midbrains of PD patients (p = 1.19E-02), and further exploration revealed that TMEM175 was also dramatically downregulated in the substantia nigra of PD patients (p = 1.16E-02) and incidental Lewy body disease patients (p = 7.52E-03). Moreover, TMEM175 was significantly downregulated in induced pluripotent stem cell-derived dopaminergic neurons from PD patients (p = 4.60E-02).
Dysregulation of TMEM175 may confer PD and LBD risk and may be partly responsible for their comorbidity. Our results revealed the common genetic risk factors between PD and LBD, which elucidated the shared genetic basis of these diseases.
帕金森病（PD）和路易体痴呆（LBD）有许多共同特征，包括临床表现、神经化学和病理学，但对于它们共有的脑蛋白和遗传因素知之甚少。
为了鉴定PD和LBD患者之间共有的易感性相关脑蛋白，通过将人类脑蛋白定量性状位点（pQTL）与这两种疾病的大规模全基因组关联研究（GWAS）相结合，进行了全蛋白质组关联研究（PWAS）。随后，进行多效性知情条件错误发现率（pleioFDR）分析，以鉴定PD和LBD之间的共同风险基因座。最后，通过差异基因表达分析验证这些风险基因在不同疾病状态下的下调情况。
PWAS鉴定出12种PD风险蛋白和9种LBD风险蛋白，其中跨膜蛋白175（TMEM175）（z = -7.25，P = 4.12E - 13；z = -6.02，P = 1.75E - 09）和2A类双C2结构域蛋白（DOC2A）（z = -4.13，P = 3.71E - 05；z = -3.91，P = 9.08E - 05）是共有的。PleioFDR分析显示，五个遗传风险位点映射到与PD和LBD相关的八个基因，包括全蛋白质组显著风险基因TMEM175（联合错误发现率ConjFDR = 5.74E - 03）。差异表达分析证实，TMEM175在PD患者的中脑中显著下调（p = 1.19E - 02），进一步研究发现，TMEM175在PD患者的黑质（p = 1.16E - 02）和路易体病患者的黑质（p = 7.52E - 03）中也显著下调。此外，TMEM175在PD患者诱导多能干细胞衍生的多巴胺能神经元中显著下调（p = 4.60E - 02）。
TMEM175的失调可能导致PD和LBD风险，可能部分解释了它们的共病现象。我们的结果揭示了PD和LBD之间的共同遗传风险因素，阐明了这些疾病的共同遗传基础。
