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.
Original language | English (US) |
---|---|
Article number | 1 |
Journal | Molecular Neurodegeneration |
Volume | 19 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2024 |
ASJC Scopus subject areas
- Molecular Biology
- Clinical Neurology
- Cellular and Molecular Neuroscience
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In: Molecular Neurodegeneration, Vol. 19, No. 1, 1, 12.2024.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease
AU - Wang, Lihua
AU - Nykänen, Niko Petteri
AU - Western, Daniel
AU - Gorijala, Priyanka
AU - Timsina, Jigyasha
AU - Li, Fuhai
AU - Wang, Zhaohua
AU - Ali, Muhammad
AU - Yang, Chengran
AU - Liu, Menghan
AU - Brock, William
AU - Marquié, Marta
AU - Boada, Mercè
AU - Alvarez, Ignacio
AU - Aguilar, Miquel
AU - Pastor, Pau
AU - Ruiz, Agustín
AU - Puerta, Raquel
AU - Orellana, Adelina
AU - Rutledge, Jarod
AU - Oh, Hamilton
AU - Greicius, Michael D.
AU - Le Guen, Yann
AU - Perrin, Richard J.
AU - Wyss-Coray, Tony
AU - Jefferson, Angela
AU - Hohman, Timothy J.
AU - Graff-Radford, Neill
AU - Mori, Hiroshi
AU - Goate, Alison
AU - Levin, Johannes
AU - Sung, Yun Ju
AU - Cruchaga, Carlos
N1 - Funding Information: This work was supported by grants from the National Institutes of Health (R01AG044546 (CC), P01AG003991 (CC, JCM), RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), RF1AG074007 (YJS)), the Chan Zuckerberg Initiative (CZI), the Michael J. Fox Foundation (CC), the Department of Defense (LI- W81XWH2010849), Centene (awarded to CC), and anonymous foundation and the Alzheimer’s Association Zenith Fellows Award (ZEN-22-848604, awarded to CC). Funding Information: ADNI resources: Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf . Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutica l Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the NeuroGenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/ ) and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Funding Information: DIAN resources: Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA),the Alzheimer’s Association (SG-20-690363-DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Funding Information: The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444 (JCM), P01AG03991 (JCM), and P01AG026276 (JCM). Funding Information: VMAP data was obtained from the Vanderbilt Memory and Aging Project. Data were collected and processed by Vanderbilt Memory and Alzheimer’s Center investigators at Vanderbilt University Medical Center funded by the following grants: R01-AG034962, R01-AG056534, R01-NS100980, R01-AG062826, and Alzheimer’s Association IIRG-08-88733. Additional funding for cerebrospinal fluid processing from the Swedish Research Council #2018-02532, the European Research Council #681712, and the Swedish State Support for Clinical Research #ALFGBG-720931. Genotyping supported by R01-AG059716. Funding Information: Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), housed at Washington University in St. Louis, is one of 30 ADRCs funded by NIH. The goal of this collaborative research effort is to advance AD research with the ultimate goal of treatment or prevention of AD. The subjects included in this study are from the Memory and Aging Project (MAP) supported by Knight ADRC. As part of the project, subjects undergo annual psychometric testing and interviews along with biennial or triennial PET, MRI and CSF collection. Further details on Knight ADRC and MAP can be found at https://knightadrc.wustl.edu/ . In our discovery stage analyses, 797 EUR samples including 178 (22.33%) of AD cases and 619 (77.67%) cognitive normal controls (hereinafter refers as controls) were from MAP cohort (Table ). In multi-ethnic fine mapping, a total of 90 non-EURs samples including 12 (13.33%) of AD cases and 78 (86.67%) controls were from MAP cohort (Table S). Funding Information: ACE Alzheimer Center Barcelona acknowledges all patients and their families for their collaboration. For CSF biomarker research, A.R. and M.B. received support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240,PI19/01301, PI22/01403 from the Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). A.R. and M.B. have also received support from CIBERNED (Instituto de Salud Carlos III (ISCIII). A.R. is also supported by the EXIT project, EU Euronanomed3 Program JCT2017, Grant No. AC17/00100 and PREADAPT project; the Joint Program for Neurodegenerative Diseases (JPND), Grant No. AC19/00097; Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and funded by Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de Hacer Europa”). I. de Rojas is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. Publisher Copyright: © 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85181260138&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85181260138&partnerID=8YFLogxK
U2 - 10.1186/s13024-023-00687-4
DO - 10.1186/s13024-023-00687-4
M3 - Article
C2 - 38172904
AN - SCOPUS:85181260138
SN - 1750-1326
VL - 19
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 1
ER -