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Cited by 366Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis

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Wingo, Aliza P., Liu, Yue, Gerasimov, Ekaterina S., Gockley, Jake, Logsdon, Benjamin A., Duong, Duc M., Dammer, Eric B., Robins, Chloe +9 more·2021·Nature Genetics
DOI 10.1038/s41588-020-00773-zPMC PMC8130821
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Abstract

Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

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  • The brain significance of ACE and CTSH reinforces the relevance of CSF to brain biology.

    “reinforcing the relevance of CSF to brain biology46.”

    From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [46]

    The introductory results identify CTSH as having evidence consistent with a causal role in Alzheimer’s disease and ACE as having mixed evidence in the brain-protein analysis (page unavailable). They do not examine CSF or establish that these findings demonstrate the relevance of CSF to brain biology. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A recent proteome-wide association study in LOAD showed that brains of LOAD patients from the ROS-MAP cohort had increased levels of RTFDC1 compared to unaffected controls.

    “This direction of effect is consistent with a recent proteome-wide association study in LOAD showing that the brains of LOAD patients from the ROS-MAP cohort presented with increased levels of RTFDC1 when compared to unaffected controls71.”

    From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [71]

    The introductory results and Methods describe a proteome-wide association study using ROS/MAP brain samples and identify RTFDC1 among proteins implicated in Alzheimer’s disease. They do not report that ROS/MAP patients with late-onset Alzheimer’s had higher measured RTFDC1 levels than unaffected controls; the reported association concerns genetically regulated protein abundance, not a direct patient–control comparison. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Wingo, A. P., Liu, Y., Gerasimov, E. S., Gockley, J., Logsdon, B. A., Duong, D. M., Dammer, E. B., Robins, C., Beach, T. G., Reiman, E. M., Epstein, M. P., De Jager, P. L., Lah, J. J., Bennett, D. A., Seyfried, N. T., Levey, A. I., & Wingo, T. S.
Affiliations
  • Emory University (US)
  • Sage Bionetworks (US)
  • Banner Sun Health Research Institute (US)
  • University of Arizona (US)
  • Rush University Medical Center (US)
Corresponding author
  • Wingo, Aliza P.
  • Wingo, Thomas S.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-01-28
Volume
53
Issue
2
Pages
143-146
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-020-00773-z
PMC
PMC8130821
OpenAlex
W3123744360
Cited by
366
References
9
Citations by year
2026: 59 · 2025: 90 · 2024: 80 · 2023: 50 · 2022: 57 · 2021: 28 · 2019: 1
FWCI
33.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 AG056533, U01 AG046152, U01 AG061356, R01 AG015819, R01 AG017917, RC2 AG036547, R01 AG053960, R01 AG057911, R01 AG061800, P30 AG066511, P30 NS055077, P50 AG025688, U01 AG046161, U01 AG061357)
  • U.S. Department of Veterans Affairs (I01 BX003853, IK4 BX005219)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, brain proteome, proteome-wide association study, genetic susceptibility loci, causal genes, cis-regulation, APOE ε4, Alzheimer's disease pathogenesis, therapeutic target
MeSH terms
Alzheimer Disease, Apolipoproteins E, Brain, Epoxide Hydrolases, Humans, Parkinson Disease, Receptors, Virus, Sequence Analysis, RNA, Proteome, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Single-Cell Analysis

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