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| Home > Articles > Published articles > Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease |
| Home > Articles > Published articles > Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease |
(Department of Psychiatry, Washington University School of Medicine) (Department of Psychiatry, Washington University School of Medicine) (Universitat Internacional de Catalunya) (Universitat Internacional de Catalunya) (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya)) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Universitat Internacional de Catalunya) (Universitat Internacional de Catalunya) (Universitat Internacional de Catalunya) (Icahn School of Medicine at Mount Sinai (Nova York, Estats Units d'Amèrica). Department of Genetics and Genomic Science) (Ludwig-Maximilians-Universität München. Department of Neurology) (Washington University School of Medicine. Hope Center for Neurological Disorders)| Date: | 2024 |
| 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; rs142232675 p. D87N, P=2. 71×10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3. 86×10) 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), 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. |
| Grants: | European Commission 681712 European Commission 115975 European Commission FI20/00215 Ministerio de Economía y Competitividad PI13/02434 Ministerio de Economía y Competitividad PI16/01861 Instituto de Salud Carlos III PI17/01474 Instituto de Salud Carlos III PI19/01240 Instituto de Salud Carlos III PI19/01301 Instituto de Salud Carlos III PI22/01403 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Alzheimer Disease ; Apolipoproteins E ; Biomarkers ; Genome-Wide Association Study ; Humans ; Membrane Glycoproteins ; Microglia ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Immunologic |
| Published in: | Molecular neurodegeneration, Vol. 19 Núm. 1 (december 2024) , p. 1, ISSN 1750-1326 |
