TY - JOUR
T1 - Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
AU - International FTD-Genomics Consortium
AU - Ge, Yi Jun
AU - Ou, Ya Nan
AU - Deng, Yue Ting
AU - Wu, Bang Sheng
AU - Yang, Liu
AU - Zhang, Ya Ru
AU - Chen, Shi Dong
AU - Huang, Yu Yuan
AU - Dong, Qiang
AU - Tan, Lan
AU - Yu, Jin Tai
AU - Ferrari, Raffaele
AU - Hernandez, Dena G.
AU - Nalls, Michael A.
AU - Rohrer, Jonathan D.
AU - Ramasamy, Adaikalavan
AU - Kwok, John B.J.
AU - Dobson-Stone, Carol
AU - Brooks, William S.
AU - Schofield, Peter R.
AU - Halliday, Glenda M.
AU - Hodges, John R.
AU - Piguet, Olivier
AU - Bartley, Lauren
AU - Thompson, Elizabeth
AU - Haan, Eric
AU - Hernández, Isabel
AU - Ruiz, Agustín
AU - Boada, Mercè
AU - Borroni, Barbara
AU - Padovani, Alessandro
AU - Cruchaga, Carlos
AU - Cairns, Nigel J.
AU - Benussi, Luisa
AU - Binetti, Giuliano
AU - Ghidoni, Roberta
AU - Forloni, Gianluigi
AU - Galimberti, Daniela
AU - Fenoglio, Chiara
AU - Serpente, Maria
AU - Scarpini, Elio
AU - Clarimón, Jordi
AU - Lleó, Alberto
AU - Blesa, Rafael
AU - Dickson, Dennis W.
AU - Graff-Radford, Neill R.
AU - Petersen, Ronald C.
AU - Knopman, David
AU - Josephs, Keith A.
AU - Boeve, Bradley F.
N1 - Publisher Copyright:
© 2022 Society of Biological Psychiatry
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Background: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. Methods: We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Results: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Conclusions: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.
AB - Background: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. Methods: We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Results: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Conclusions: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.
KW - Drug discovery
KW - Genetics
KW - Mendelian randomization
KW - Neurodegenerative disease
KW - Omics
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85148707123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148707123&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2022.11.002
DO - 10.1016/j.biopsych.2022.11.002
M3 - Article
C2 - 36759259
AN - SCOPUS:85148707123
SN - 0006-3223
VL - 93
SP - 770
EP - 779
JO - Biological psychiatry
JF - Biological psychiatry
IS - 9
ER -