Advertisement

Prioritization of drug targets for neurodegenerative diseases by integrating genetic and proteomic data from brain and blood

  • Author Footnotes
    † These authors contributed equally to this work.
    Yi-Jun Ge
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this work.
    Ya-Nan Ou
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
    Search for articles by this author
  • Yue-Ting Deng
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Bang-Sheng Wu
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Liu Yang
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Ya-Ru Zhang
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Shi-Dong Chen
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Yu-Yuan Huang
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Qiang Dong
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • Lan Tan
    Affiliations
    Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
    Search for articles by this author
  • Jin-Tai Yu
    Correspondence
    Correspondence to: Prof. Jin-Tai Yu, MD, PhD, National Center for Neurological Disorders in China, Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China, Tel: +86 21 52888160; Fax: +86 21 62483421.
    Affiliations
    Department of Neurology and Institute of Neurology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
    Search for articles by this author
  • theInternational FTD-Genomics Consortium (IFGC)
  • Author Footnotes
    † These authors contributed equally to this work.
Published:November 09, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.11.002

      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 access
      One-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 Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Villoslada P.
        • Baeza-Yates R.
        • Masdeu J.C.
        Reclassifying neurodegenerative diseases.
        Nat Biomed Eng. 2020; 4: 759-760
        • The Lancet N.
        Joining forces to fight neurodegenerative diseases.
        The Lancet Neurology. 2013; 12: 119
        • Alteri E.
        • Guizzaro L.
        Be open about drug failures to speed up research.
        Nature. 2018; 563: 317-319
        • Nelson M.R.
        • Tipney H.
        • Painter J.L.
        • Shen J.
        • Nicoletti P.
        • Shen Y.
        • et al.
        The support of human genetic evidence for approved drug indications.
        Nat Genet. 2015; 47: 856-860
        • Sun B.B.
        • Maranville J.C.
        • Peters J.E.
        • Stacey D.
        • Staley J.R.
        • Blackshaw J.
        • et al.
        Genomic atlas of the human plasma proteome.
        Nature. 2018; 558: 73-79
        • Robins C.
        • Liu Y.
        • Fan W.
        • Duong D.M.
        • Meigs J.
        • Harerimana N.V.
        • et al.
        Genetic control of the human brain proteome.
        The American Journal of Human Genetics. 2021; 108: 400-410
        • Zhou S.
        • Butler-Laporte G.
        • Nakanishi T.
        • Morrison D.R.
        • Afilalo J.
        • Afilalo M.
        • et al.
        A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.
        Nature medicine. 2021; 27: 659-667
        • Bennett D.A.
        • Buchman A.S.
        • Boyle P.A.
        • Barnes L.L.
        • Wilson R.S.
        • Schneider J.A.
        Religious Orders Study and Rush Memory and Aging Project.
        Journal of Alzheimer's disease : JAD. 2018; 64: S161-s189
        • Wingo A.P.
        • Liu Y.
        • Gerasimov E.S.
        • Gockley J.
        • Logsdon B.A.
        • Duong D.M.
        • et al.
        Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis.
        Nat Genet. 2021; 53: 143-146
        • Higginbotham L.
        • Ping L.
        • Dammer E.B.
        • Duong D.M.
        • Zhou M.
        • Gearing M.
        • et al.
        Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer's disease.
        Sci Adv. 2020; 6
        • Suhre K.
        • Arnold M.
        • Bhagwat A.M.
        • Cotton R.J.
        • Engelke R.
        • Raffler J.
        • et al.
        Connecting genetic risk to disease end points through the human blood plasma proteome.
        Nature communications. 2017; 814357
        • Emilsson V.
        • Ilkov M.
        • Lamb J.R.
        • Finkel N.
        • Gudmundsson E.F.
        • Pitts R.
        • et al.
        Co-regulatory networks of human serum proteins link genetics to disease.
        Science (New York, NY). 2018; 361: 769-773
        • Battle A.
        • Brown C.D.
        • Engelhardt B.E.
        • Montgomery S.B.
        Genetic effects on gene expression across human tissues.
        Nature. 2017; 550: 204-213
        • Schwartzentruber J.
        • Cooper S.
        • Liu J.Z.
        • Barrio-Hernandez I.
        • Bello E.
        • Kumasaka N.
        • et al.
        Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.
        Nat Genet. 2021; 53: 392-402
        • Nalls M.A.
        • Blauwendraat C.
        • Vallerga C.L.
        • Heilbron K.
        • Bandres-Ciga S.
        • Chang D.
        • et al.
        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
        • van Rheenen W.
        • van der Spek R.A.A.
        • Bakker M.K.
        • van Vugt J.
        • Hop P.J.
        • Zwamborn R.A.J.
        • et al.
        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
      1. 2019): Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science (New York, NY). 365.

        • Ferrari R.
        • Hernandez D.G.
        • Nalls M.A.
        • Rohrer J.D.
        • Ramasamy A.
        • Kwok J.B.J.
        • et al.
        Frontotemporal dementia and its subtypes: a genome-wide association study.
        The Lancet Neurology. 2014; 13: 686-699
        • Chia R.
        • Sabir M.S.
        • Bandres-Ciga S.
        • Saez-Atienzar S.
        • Reynolds R.H.
        • Gustavsson E.
        • et al.
        Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.
        Nat Genet. 2021; 53: 294-303
        • Kamat M.A.
        • Blackshaw J.A.
        • Young R.
        • Surendran P.
        • Burgess S.
        • Danesh J.
        • et al.
        PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.
        Bioinformatics. 2019; 35: 4851-4853
        • Staley J.R.
        • Blackshaw J.
        • Kamat M.A.
        • Ellis S.
        • Surendran P.
        • Sun B.B.
        • et al.
        PhenoScanner: a database of human genotype-phenotype associations.
        Bioinformatics. 2016; 32: 3207-3209
        • Folkersen L.
        • Fauman E.
        • Sabater-Lleal M.
        • Strawbridge R.J.
        • Frånberg M.
        • Sennblad B.
        • et al.
        Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.
        PLoS genetics. 2017; 13e1006706
        • Yao C.
        • Chen G.
        • Song C.
        • Keefe J.
        • Mendelson M.
        • Huan T.
        • et al.
        Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.
        Nature communications. 2018; 9: 3268
        • Yang C.
        • Farias F.H.G.
        • Ibanez L.
        • Suhy A.
        • Sadler B.
        • Fernandez M.V.
        • et al.
        Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders.
        Nat Neurosci. 2021;
        • Davies N.M.
        • Holmes M.V.
        • Davey Smith G.
        Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians.
        BMJ. 2018; 362k601
        • Burgess S.
        • Dudbridge F.
        • Thompson S.G.
        Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods.
        Stat Med. 2016; 35: 1880-1906
        • Burgess S.
        • Davey Smith G.
        • Davies N.
        • Dudbridge F.
        • Gill D.
        • Glymour M.
        • et al.
        Guidelines for performing Mendelian randomization investigations [version 2; peer review: 2 approved].
        Wellcome Open Research. 2020; 4
        • Hemani G.
        • Zheng J.
        • Elsworth B.
        • Wade K.H.
        • Haberland V.
        • Baird D.
        • et al.
        The MR-Base platform supports systematic causal inference across the human phenome.
        Elife. 2018; 7
        • Ward L.D.
        • Kellis M.
        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
        • Elsworth B.
        • Lyon M.
        • Alexander T.
        • Liu Y.
        • Matthews P.
        • Hallett J.
        • et al.
        The MRC IEU OpenGWAS data infrastructure.
        bioRxiv. 2020; (2020.2008.2010)244293
        • Finan C.
        • Gaulton A.
        • Kruger F.A.
        • Lumbers R.T.
        • Shah T.
        • Engmann J.
        • et al.
        The druggable genome and support for target identification and validation in drug development.
        Sci Transl Med. 2017; 9
        • Wishart D.S.
        • Feunang Y.D.
        • Guo A.C.
        • Lo E.J.
        • Marcu A.
        • Grant J.R.
        • et al.
        DrugBank 5.0: a major update to the DrugBank database for 2018.
        Nucleic Acids Res. 2018; 46: D1074-d1082
        • Emmerich C.H.
        • Gamboa L.M.
        • Hofmann M.C.J.
        • Bonin-Andresen M.
        • Arbach O.
        • Schendel P.
        • et al.
        Improving target assessment in biomedical research: the GOT-IT recommendations.
        Nat Rev Drug Discov. 2021; 20: 64-81
        • Kunkle B.W.
        • Grenier-Boley B.
        • Sims R.
        • Bis J.C.
        • Damotte V.
        • Naj A.C.
        • et al.
        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
        • den Brok M.
        • van Dalen J.W.
        • Abdulrahman H.
        • Larson E.B.
        • van Middelaar T.
        • van Gool W.A.
        • et al.
        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
        • Guan Z.
        • Chen Z.
        • Fu S.
        • Dai L.
        • Shen Y.
        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
      2. 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.

        • Moloney E.B.
        • Moskites A.
        • Ferrari E.J.
        • Isacson O.
        • Hallett P.J.
        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
        • Cui X.
        • Liu C.M.
        • Liu Q.B.
        FCRL3 promotes IL-10 expression in B cells through the SHP-1 and p38 MAPK signaling pathways.
        Cell Biol Int. 2020; 44: 1811-1819
        • Endo S.
        • Miyagi N.
        • Matsunaga T.
        • Hara A.
        • Ikari A.
        Human dehydrogenase/reductase (SDR family) member 11 is a novel type of 17β-hydroxysteroid dehydrogenase.
        Biochem Biophys Res Commun. 2016; 472: 231-236
        • Deeb O.
        • Nabulsi M.
        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
        • Zheng J.
        • Haberland V.
        • Baird D.
        • Walker V.
        • Haycock P.C.
        • Hurle M.R.
        • et al.
        Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.
        Nat Genet. 2020; 52: 1122-1131
        • Kia D.A.
        • Zhang D.
        • Guelfi S.
        • Manzoni C.
        • Hubbard L.
        • Reynolds R.H.
        • et al.
        Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets.
        JAMA neurology. 2021; 78: 464-472