Back to Publications​
Publication
Molecular Neurodegeneration

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

Back to Publications​
  • January 3, 2024
  • Carlos Cruchaga, et al., Washington University, St. Louis
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
CSF

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.

Read the Publication

Authors & Affiliations

Authors

Lihua Wang¹²†, Niko-Petteri Nykänen¹²†, Daniel Western¹², Priyanka Gorijala¹², Jigyasha Timsina¹², Fuhai Li³, Zhaohua Wang¹², Muhammad Ali¹², Chengran Yang¹², Menghan Liu¹², William Brock¹², Marta Marquié⁴⁵, Mercè Boada⁴⁵, Ignacio Alvarez⁶, Miquel Aguilar⁶, Pau Pastor⁷, Agustín Ruiz⁴⁵, Raquel Puerta⁴⁵, Adelina Orellana⁴⁵, Jarod Rutledge⁸, Hamilton Oh⁸, Michael D. Greicius⁸, Yann Le Guen⁸, Richard J. Perrin⁹, Tony Wyss-Coray⁸, Angela Jefferson¹⁰, Timothy J. Hohman¹⁰, Neill Graff-Radford¹¹, Hiroshi Mori¹², Alison Goate¹³, Johannes Levin¹⁴, Yun Ju Sung¹²¹⁵, and Carlos Cruchaga¹²¹⁶*

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA
³ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
⁴ Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
⁵ Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
⁶ Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain
⁷ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain
⁸ Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
⁹ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
¹⁰ Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
¹¹ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
¹² Nagaoka Sutoku University, Osaka, Japan
¹³ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
¹⁴ Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
¹⁵ Division of Biostatistics, Washington University School of Medicine, BJC Institute of Health, St. Louis, MO, USA
¹⁶ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, USA

Linkedin

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Linkedin

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.