Identification of Common Brain Protein and Genetic Loci Between Parkinson's Disease and Lewy Body Dementia

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_PD = -7.25, P_PD = 4.12E-13; z_LBD = -6.02, P_LBD = 1.75E-09) and DOC2A (z_PD = -4.13, P_PD = 3.71E-05; z_LBD = -3.91, P_LBD = 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.