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Mapping the serum proteome to neurological diseases using whole genome sequencing

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Png, Grace, Barysenka, Andrei, Repetto, Linda, Navarro, Pau, Shen, Xia, Pietzner, Maik, Wheeler, Eleanor, Wareham, Nicholas J. +8 more·2021·Nature Communications
DOI 10.1038/s41467-021-27387-1PMC PMC8640022
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Abstract

Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer’s disease, GPNMB and Parkinson’s disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

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Authors
Png, G., Barysenka, A., Repetto, L., Navarro, P., Shen, X., Pietzner, M., Wheeler, E., Wareham, N. J., Langenberg, C., Tsafantakis, E., Karaleftheri, M., Dedoussis, G., Mälarstig, A., Wilson, J. F., Gilly, A., & Zeggini, E.
Affiliations
  • TUM Klinikum (DE)
  • Helmholtz Munich (DE)
  • University of Edinburgh (GB)
  • Institute of Genetics and Cancer (GB)
  • Fudan University (CN)
  • University of Cambridge (GB)
  • Harokopio University of Athens (GR)
  • Pfizer (United States) (US)
Corresponding author
  • Png, Grace
  • Zeggini, Eleftheria
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-12-02
Volume
12
Issue
1
Pages
7042-7042
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-27387-1
PMC
PMC8640022
OpenAlex
W3217370940
Cited by
55
References
11
Citations by year
2026: 2 · 2025: 14 · 2024: 10 · 2023: 18 · 2022: 11
FWCI
5.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Apollo (cc-by)
  • Apollo
Funders
  • Wellcome Trust (098051)
  • Broad Institute
  • University of Cambridge (00001)
  • European Commission
  • Medical Research Council (MC_UU_12015/1, MC_PC_13046, MC_UU_12015, 098051, MC_UU_00007/10)
  • European Social Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Keywords
serum proteome, neurological disorders, quantitative trait loci, genetic variants, circulating proteins, Alzheimer's disease, Parkinson's disease, schizophrenia, CD33, GPNMB, MSR1, biomarkers, drug repurposing, Mendelian randomization, cis-acting variants
MeSH terms
Whole Genome Sequencing, Alzheimer Disease, Humans, Membrane Glycoproteins, Parkinson Disease, Schizophrenia, Cohort Studies, Biomarkers, Gene Expression, Genome, Human, Genetic Predisposition to Disease, Proteome, Quantitative Trait Loci, Scavenger Receptors, Class A, Mendelian Randomization Analysis, Molecular Sequence Annotation, Sialic Acid Binding Ig-like Lectin 3, Gene Ontology

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