Journal article
Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
Biological psychiatry (1969), Vol.93(9), pp.770-779
05/01/2023
DOI: 10.1016/j.biopsych.2022.11.002
PMCID: PMC12272336
PMID: 36759259
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
- Creators
- Yi-Jun Ge - Qingdao Municipal HospitalYa-Nan Ou - Qingdao UniversityYue-Ting Deng - Shanghai Medical College of Fudan UniversityBang-Sheng Wu - Shanghai Medical College of Fudan UniversityLiu Yang - Shanghai Medical College of Fudan UniversityYa-Ru Zhang - Shanghai Medical College of Fudan UniversityShi-Dong Chen - Huashan HospitalYu-Yuan Huang - Shanghai Medical College of Fudan UniversityQiang Dong - Huashan HospitalLan Tan - Qingdao Municipal HospitalJin-Tai Yu - Shanghai Medical College of Fudan UniversityInternational FTD-Genomics ConsortiumTimothy Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- Biological psychiatry (1969), Vol.93(9), pp.770-779
- DOI
- 10.1016/j.biopsych.2022.11.002
- PMID
- 36759259
- PMCID
- PMC12272336
- NLM abbreviation
- Biol Psychiatry
- ISSN
- 0006-3223
- eISSN
- 1873-2402
- Grant note
- MR/M008983/1 / Medical Research Council MR/L023784/2 / Medical Research Council MR/M023664/1 / Medical Research Council MC_UU_00030/14 / Medical Research Council G0301152 / Medical Research Council MC_U105597119 / Medical Research Council MR/T033371/1 / Medical Research Council MR/M008525/1 / Medical Research Council MC_UU_00005/12 / Medical Research Council MR/T046015/1 / Medical Research Council
- Language
- English
- Date published
- 05/01/2023
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627184602771
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