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

Autor: Wang L; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Nykänen NP; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Western D; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Gorijala P; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Timsina J; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Li F; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA., Wang Z; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Ali M; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Yang C; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Liu M; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Brock W; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA., Marquié M; Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain., Boada M; Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain., Alvarez I; Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain., Aguilar M; Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain., Pastor P; Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain., Ruiz A; Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain., Puerta R; Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain., Orellana A; Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain., Rutledge J; Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Oh H; Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Greicius MD; Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Le Guen Y; Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Perrin RJ; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA., Wyss-Coray T; Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Jefferson A; Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA., Hohman TJ; Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA., Graff-Radford N; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Mori H; Nagaoka Sutoku University, Osaka, Japan., Goate A; Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Levin J; Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany., Sung YJ; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.; Division of Biostatistics, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave, Box 8134, St. Louis, MO, 63110, USA., Cruchaga C; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.; NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA. cruchagac@wustl.edu.; Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA. cruchagac@wustl.edu.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2024 Jan 03; Vol. 19 (1), pp. 1. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1186/s13024-023-00687-4
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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