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 (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.

Authors and Affiliations
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Lihua Wang, Niko-Petteri Nykänen, Daniel Western, Priyanka Gorijala, Jigyasha Timsina, Zhaohua Wang, Muhammad Ali, Chengran Yang, Menghan Liu, William Brock, Yun Ju Sung & Carlos Cruchaga

NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA
Lihua Wang, Niko-Petteri Nykänen, Daniel Western, Priyanka Gorijala, Jigyasha Timsina, Zhaohua Wang, Muhammad Ali, Chengran Yang, Menghan Liu, William Brock, Yun Ju Sung & Carlos Cruchaga

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
Fuhai Li

Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Marta Marquié, Mercè Boada, Agustín Ruiz, Raquel Puerta & Adelina Orellana

Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
Marta Marquié, Mercè Boada, Agustín Ruiz, Raquel Puerta & Adelina Orellana

Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain
Ignacio Alvarez & Miquel Aguilar

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
Pau Pastor

Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
Jarod Rutledge, Hamilton Oh, Michael D Greicius, Yann Le Guen & Tony Wyss-Coray

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
Richard J. Perrin

Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
Angela Jefferson & Timothy J. Hohman

Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
Neill Graff-Radford

Nagaoka Sutoku University, Osaka, Japan
Hiroshi Mori

Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Alison Goate

Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
Johannes Levin

Division of Biostatistics, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave, Box 8134, St. Louis, MO, 63110, USA
Yun Ju Sung

Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA
Carlos Cruchaga