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Cited by 58Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsMultiple Sclerosis Research Studies

Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease

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Wang, Lihua, Nykänen, Niko-Petteri, Western, Daniel, Gorijala, Priyanka, Timsina, Jigyasha, Li, Fuhai, Wang, Zhaohua, Ali, Muhammad +25 more·2024·Molecular Neurodegeneration
DOI 10.1186/s13024-023-00687-4PMC PMC10763080

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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A ) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P =7.16×10 -19 ; rs142232675 p.D87N, P =2.71×10 -10 ) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P =3.86×10 -9 ) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2 . Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P =2.52×10 -8 ), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

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Authors
Wang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., Brock, W., Marquié, M., Boada, M., Alvarez, I., Aguilar, M., Pastor, P., Ruiz, A., Puerta, R., Orellana, A., Rutledge, J., Oh, H., Greicius, M. D., Le Guen, Y., Perrin, R. J., Wyss-Coray, T., Jefferson, A., Hohman, T. J., Graff-Radford, N., Mori, H., Goate, A., Levin, J., Sung, Y. J., & Cruchaga, C.
Affiliations
  • Washington University in St. Louis (US)
  • Instituto de Salud Carlos III (ES)
  • University Hospital Mútua de Terrassa (ES)
  • Stanford University (US)
  • Vanderbilt University Medical Center (US)
  • Nagaoka Sutoku University (JP)
  • Icahn School of Medicine at Mount Sinai (US)
  • LMU Klinikum (DE)
Corresponding author
Cruchaga, Carlos
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2024-01-03
Volume
19
Issue
1
Pages
1-1
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-023-00687-4
PMC
PMC10763080
OpenAlex
W4390571517
Cited by
58
References
24
Citations by year
2026: 21 · 2025: 21 · 2024: 14 · 2023: 1 · 2021: 1
FWCI
8.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • medRxiv (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • PUBLISSO (German National Library of Medicine) (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIA (R01AG044546)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
soluble TREM2, cerebrospinal fluid biomarkers, Alzheimer's disease, genetic modifiers, MS4A4A, MS4A6A, TGFBR2, RBMS3, nectin-2, apolipoprotein E, microglia, epistasis, genetic variants, proteogenomics, neuroinflammation
MeSH terms
Receptor, Transforming Growth Factor-beta Type II, Alzheimer Disease, Apolipoproteins E, Humans, Membrane Glycoproteins, Receptors, Immunologic, Biomarkers, Microglia, Genome-Wide Association Study

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