Abstract
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 (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis
(ALS), multiple sclerosis (MS), frontotemporal dementia, and Lewy body dementia. For
instruments, we used brain and blood protein quantitative trait loci (pQTLs) identified
from one GWAS with 376 individuals and another with 3,301, 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 AD 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 PD. Among them, GPNMB was the most promising target for PD with their causal relationship
evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3,
LMAN2, MAPK3 in blood and DHRS11, FAM120B, SHMT1, TSFM in brain might affect MS risk.
The risk of ALS 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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Reclassifying neurodegenerative diseases.Nat Biomed Eng. 2020; 4: 759-760
- Joining forces to fight neurodegenerative diseases.The Lancet Neurology. 2013; 12: 119
- Be open about drug failures to speed up research.Nature. 2018; 563: 317-319
- The support of human genetic evidence for approved drug indications.Nat Genet. 2015; 47: 856-860
- Genomic atlas of the human plasma proteome.Nature. 2018; 558: 73-79
- Genetic control of the human brain proteome.The American Journal of Human Genetics. 2021; 108: 400-410
- A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.Nature medicine. 2021; 27: 659-667
- Religious Orders Study and Rush Memory and Aging Project.Journal of Alzheimer's disease : JAD. 2018; 64: S161-s189
- Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.Nat Genet. 2021; 53: 143-146
- Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease.Sci Adv. 2020; 6
- Connecting genetic risk to disease end points through the human blood plasma proteome.Nature communications. 2017; 814357
- Co-regulatory networks of human serum proteins link genetics to disease.Science (New York, NY). 2018; 361: 769-773
- Genetic effects on gene expression across human tissues.Nature. 2017; 550: 204-213
- Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.Nat Genet. 2021; 53: 392-402
- Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.The Lancet Neurology. 2019; 18: 1091-1102
- Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.Nat Genet. 2021; 53: 1636-1648
2019): Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science (New York, NY). 365.
- Frontotemporal dementia and its subtypes: a genome-wide association study.The Lancet Neurology. 2014; 13: 686-699
- Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.Nat Genet. 2021; 53: 294-303
- PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.Bioinformatics. 2019; 35: 4851-4853
- PhenoScanner: a database of human genotype-phenotype associations.Bioinformatics. 2016; 32: 3207-3209
- Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.PLoS genetics. 2017; 13e1006706
- Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.Nature communications. 2018; 9: 3268
- Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders.Nat Neurosci. 2021;
- Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.BMJ. 2018; 362k601
- Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods.Stat Med. 2016; 35: 1880-1906
- Guidelines for performing Mendelian randomization investigations [version 2; peer review: 2 approved].Wellcome Open Research. 2020; 4
- The MR-Base platform supports systematic causal inference across the human phenome.Elife. 2018; 7
- HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants.Nucleic Acids Res. 2012; 40: D930-934
- The MRC IEU OpenGWAS data infrastructure.bioRxiv. 2020; (2020.2008.2010)244293
- The druggable genome and support for target identification and validation in drug development.Sci Transl Med. 2017; 9
- DrugBank 5.0: a major update to the DrugBank database for 2018.Nucleic Acids Res. 2018; 46: D1074-d1082
- Improving target assessment in biomedical research: the GOT-IT recommendations.Nat Rev Drug Discov. 2021; 20: 64-81
- Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.Nat Genet. 2019; 51: 414-430
- Antihypertensive Medication Classes and the Risk of Dementia: A Systematic Review and Network Meta-Analysis.J Am Med Dir Assoc. 2021; 22 (e1315): 1386-1395
- Progranulin Administration Attenuates β-Amyloid Deposition in the Hippocampus of 5xFAD Mice Through Modulating BACE1 Expression and Microglial Phagocytosis.Front Cell Neurosci. 2020; 14: 260
Diaz-Ortiz ME, Seo Y, Posavi M, Carceles Cordon M, Clark E, Jain N, et al. (2022): GPNMB confers risk for Parkinson’s disease through interaction with a-synuclein. Science (New York, NY). 377:eabk0637.
- The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson's disease patients and increases after lysosomal stress.Neurobiol Dis. 2018; 120: 1-11
- FCRL3 promotes IL-10 expression in B cells through the SHP-1 and p38 MAPK signaling pathways.Cell Biol Int. 2020; 44: 1811-1819
- Human dehydrogenase/reductase (SDR family) member 11 is a novel type of 17β-hydroxysteroid dehydrogenase.Biochem Biophys Res Commun. 2016; 472: 231-236
- Exploring Multiple Sclerosis (MS) and Amyotrophic Lateral Scler osis (ALS) as Neurodegenerative Diseases and their Treatments: A Review Study.Curr Top Med Chem. 2020; 20: 2391-2403
- Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.Nat Genet. 2020; 52: 1122-1131
- Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets.JAMA neurology. 2021; 78: 464-472
Article Info
Publication History
Accepted:
November 2,
2022
Received in revised form:
October 29,
2022
Received:
May 12,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
