Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease
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 (...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-01-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | https://doi.org/10.1186/s13024-023-00687-4 |
| _version_ | 1827388139830771712 |
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| author | Lihua Wang Niko-Petteri Nykänen Daniel Western Priyanka Gorijala Jigyasha Timsina Fuhai Li Zhaohua Wang Muhammad Ali Chengran Yang Menghan Liu William Brock Marta Marquié Mercè Boada Ignacio Alvarez Miquel Aguilar Pau Pastor Agustín Ruiz Raquel Puerta Adelina Orellana Jarod Rutledge Hamilton Oh Michael D Greicius Yann Le Guen Richard J. Perrin Tony Wyss-Coray Angela Jefferson Timothy J. Hohman Neill Graff-Radford Hiroshi Mori Alison Goate Johannes Levin Yun Ju Sung Carlos Cruchaga |
| author_facet | Lihua Wang Niko-Petteri Nykänen Daniel Western Priyanka Gorijala Jigyasha Timsina Fuhai Li Zhaohua Wang Muhammad Ali Chengran Yang Menghan Liu William Brock Marta Marquié Mercè Boada Ignacio Alvarez Miquel Aguilar Pau Pastor Agustín Ruiz Raquel Puerta Adelina Orellana Jarod Rutledge Hamilton Oh Michael D Greicius Yann Le Guen Richard J. Perrin Tony Wyss-Coray Angela Jefferson Timothy J. Hohman Neill Graff-Radford Hiroshi Mori Alison Goate Johannes Levin Yun Ju Sung Carlos Cruchaga |
| author_sort | Lihua Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:13:22Z |
| format | Article |
| id | doaj.art-7186895a6614490394229c23126dc1de |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-03-08T16:13:22Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-7186895a6614490394229c23126dc1de2024-01-07T12:46:56ZengBMCMolecular Neurodegeneration1750-13262024-01-0119112510.1186/s13024-023-00687-4Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s diseaseLihua Wang0Niko-Petteri Nykänen1Daniel Western2Priyanka Gorijala3Jigyasha Timsina4Fuhai Li5Zhaohua Wang6Muhammad Ali7Chengran Yang8Menghan Liu9William Brock10Marta Marquié11Mercè Boada12Ignacio Alvarez13Miquel Aguilar14Pau Pastor15Agustín Ruiz16Raquel Puerta17Adelina Orellana18Jarod Rutledge19Hamilton Oh20Michael D Greicius21Yann Le Guen22Richard J. Perrin23Tony Wyss-Coray24Angela Jefferson25Timothy J. Hohman26Neill Graff-Radford27Hiroshi Mori28Alison Goate29Johannes Levin30Yun Ju Sung31Carlos Cruchaga32Department of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineNetworking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos IIINetworking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos IIIMemory Disorders Unit, Department of Neurology, University Hospital Mutua TerrassaMemory Disorders Unit, Department of Neurology, University Hospital Mutua TerrassaUnit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) BadalonaNetworking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos IIINetworking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos IIINetworking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos IIIWu-Tsai Neurosciences Institute, Stanford UniversityWu-Tsai Neurosciences Institute, Stanford UniversityWu-Tsai Neurosciences Institute, Stanford UniversityWu-Tsai Neurosciences Institute, Stanford UniversityDepartment of Pathology & Immunology, Washington University School of MedicineWu-Tsai Neurosciences Institute, Stanford UniversityVanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical CenterVanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical CenterDepartment of Neurology, Mayo ClinicNagaoka Sutoku UniversityDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) MunichDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineAbstract 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.https://doi.org/10.1186/s13024-023-00687-4 |
| spellingShingle | Lihua Wang Niko-Petteri Nykänen Daniel Western Priyanka Gorijala Jigyasha Timsina Fuhai Li Zhaohua Wang Muhammad Ali Chengran Yang Menghan Liu William Brock Marta Marquié Mercè Boada Ignacio Alvarez Miquel Aguilar Pau Pastor Agustín Ruiz Raquel Puerta Adelina Orellana Jarod Rutledge Hamilton Oh Michael D Greicius Yann Le Guen Richard J. Perrin Tony Wyss-Coray Angela Jefferson Timothy J. Hohman Neill Graff-Radford Hiroshi Mori Alison Goate Johannes Levin Yun Ju Sung Carlos Cruchaga Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease Molecular Neurodegeneration |
| title | Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease |
| title_full | Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease |
| title_fullStr | Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease |
| title_full_unstemmed | Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease |
| title_short | Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease |
| title_sort | proteo genomics of soluble trem2 in cerebrospinal fluid provides novel insights and identifies novel modulators for alzheimer s disease |
| url | https://doi.org/10.1186/s13024-023-00687-4 |
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