Janet Cady1, Erica D Koval1, Bruno A Benitez2, Craig Zaidman1, Jennifer Jockel-Balsarotti1, Peggy Allred3, Robert H Baloh4, John Ravits5, Ericka Simpson6, Stanley H Appel6, Alan Pestronk1, Alison M Goate7, Timothy M Miller8, Carlos Cruchaga9, Matthew B Harms8. 1. Department of Neurology, Washington University School of Medicine, St Louis, Missouri. 2. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri. 3. Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California. 4. Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California4Department of Neurology, University of California, Los Angeles. 5. Department of Neurosciences, University of California, San Diego, La Jolla, California. 6. Department of Neurology, Methodist Neurological Institute, Methodist Research Institute, The Methodist Hospital, Houston, Texas. 7. Department of Neurology, Washington University School of Medicine, St Louis, Missouri2Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine. 8. Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri. 9. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri.
Abstract
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease. Whether the p.R47H variant is a risk factor for ALS is not known. OBJECTIVES: To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. DESIGN, SETTING, AND PARTICIPANTS: Samples of DNA from 923 individuals with sporadic ALS and 1854 healthy control individuals self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data were obtained on ALS participants for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative polymerase chain reaction and compared in spinal cord samples from 18 autopsied patients with ALS and 12 neurologically healthy controls, as well as from wild-type and transgenic SOD1G93A mice. MAIN OUTCOMES AND MEASURES: Minor allele frequency of rs75932628 and relative expression of TREM2. RESULTS: The TREM2 variant p.R47H was more common in patients with ALS than in the controls and is therefore a significant risk factor for ALS (odds ratio, 2.40; 95% CI, 1.29-4.15; P = 4.1×10-3). Furthermore, TREM2 expression was increased in spinal cord samples from ALS patients and SOD1G93A mice (P = 2.8×10-4 and P = 2.8×10-9, respectively), confirming dysregulated TREM2 in disease. Expression of TREM2 in the human spinal cord was negatively correlated with survival (P = .04) but not with other phenotypic aspects of disease. CONCLUSIONS AND RELEVANCE: This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic ALS. To our knowledge, these findings identify the first genetic influence on neuroinflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease. Whether the p.R47H variant is a risk factor for ALS is not known. OBJECTIVES: To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. DESIGN, SETTING, AND PARTICIPANTS: Samples of DNA from 923 individuals with sporadic ALS and 1854 healthy control individuals self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data were obtained on ALSparticipants for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative polymerase chain reaction and compared in spinal cord samples from 18 autopsied patients with ALS and 12 neurologically healthy controls, as well as from wild-type and transgenicSOD1G93Amice. MAIN OUTCOMES AND MEASURES: Minor allele frequency of rs75932628 and relative expression of TREM2. RESULTS: The TREM2 variant p.R47H was more common in patients with ALS than in the controls and is therefore a significant risk factor for ALS (odds ratio, 2.40; 95% CI, 1.29-4.15; P = 4.1×10-3). Furthermore, TREM2 expression was increased in spinal cord samples from ALSpatients and SOD1G93Amice (P = 2.8×10-4 and P = 2.8×10-9, respectively), confirming dysregulated TREM2 in disease. Expression of TREM2 in the human spinal cord was negatively correlated with survival (P = .04) but not with other phenotypic aspects of disease. CONCLUSIONS AND RELEVANCE: This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic ALS. To our knowledge, these findings identify the first genetic influence on neuroinflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.
Authors: Josue D Gonzalez Murcia; Cameron Schmutz; Caitlin Munger; Ammon Perkes; Aaron Gustin; Michael Peterson; Mark T W Ebbert; Maria C Norton; Joann T Tschanz; Ronald G Munger; Christopher D Corcoran; John S K Kauwe Journal: Neurobiol Aging Date: 2013-07-12 Impact factor: 4.673
Authors: J Paloneva; M Kestilä; J Wu; A Salminen; T Böhling; V Ruotsalainen; P Hakola; A B Bakker; J H Phillips; P Pekkarinen; L L Lanier; T Timonen; L Peltonen Journal: Nat Genet Date: 2000-07 Impact factor: 38.330
Authors: Thorlakur Jonsson; Hreinn Stefansson; Stacy Steinberg; Ingileif Jonsdottir; Palmi V Jonsson; Jon Snaedal; Sigurbjorn Bjornsson; Johanna Huttenlocher; Allan I Levey; James J Lah; Dan Rujescu; Harald Hampel; Ina Giegling; Ole A Andreassen; Knut Engedal; Ingun Ulstein; Srdjan Djurovic; Carla Ibrahim-Verbaas; Albert Hofman; M Arfan Ikram; Cornelia M van Duijn; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: N Engl J Med Date: 2012-11-14 Impact factor: 91.245
Authors: Rita João Guerreiro; Ebba Lohmann; José Miguel Brás; Jesse Raphael Gibbs; Jonathan D Rohrer; Nicole Gurunlian; Burcu Dursun; Basar Bilgic; Hasmet Hanagasi; Hakan Gurvit; Murat Emre; Andrew Singleton; John Hardy Journal: JAMA Neurol Date: 2013-01 Impact factor: 18.302
Authors: Bruno A Benitez; Breanna Cooper; Pau Pastor; Sheng-Chih Jin; Elena Lorenzo; Sebastian Cervantes; Carlos Cruchaga Journal: Neurobiol Aging Date: 2013-02-05 Impact factor: 4.673
Authors: Sruti Rayaprolu; Bianca Mullen; Matt Baker; Timothy Lynch; Elizabeth Finger; William W Seeley; Kimmo J Hatanpaa; Catherine Lomen-Hoerth; Andrew Kertesz; Eileen H Bigio; Carol Lippa; Keith A Josephs; David S Knopman; Charles L White; Richard Caselli; Ian R Mackenzie; Bruce L Miller; Magdalena Boczarska-Jedynak; Grzegorz Opala; Anna Krygowska-Wajs; Maria Barcikowska; Steven G Younkin; Ronald C Petersen; Nilüfer Ertekin-Taner; Ryan J Uitti; James F Meschia; Kevin B Boylan; Bradley F Boeve; Neill R Graff-Radford; Zbigniew K Wszolek; Dennis W Dickson; Rosa Rademakers; Owen A Ross Journal: Mol Neurodegener Date: 2013-06-21 Impact factor: 14.195
Authors: Johannes Brettschneider; Jon B Toledo; Vivianna M Van Deerlin; Lauren Elman; Leo McCluskey; Virginia M-Y Lee; John Q Trojanowski Journal: PLoS One Date: 2012-06-14 Impact factor: 3.240
Authors: Rita Guerreiro; Aleksandra Wojtas; Jose Bras; Minerva Carrasquillo; Ekaterina Rogaeva; Elisa Majounie; Carlos Cruchaga; Celeste Sassi; John S K Kauwe; Steven Younkin; Lilinaz Hazrati; John Collinge; Jennifer Pocock; Tammaryn Lashley; Julie Williams; Jean-Charles Lambert; Philippe Amouyel; Alison Goate; Rosa Rademakers; Kevin Morgan; John Powell; Peter St George-Hyslop; Andrew Singleton; John Hardy Journal: N Engl J Med Date: 2012-11-14 Impact factor: 91.245
Authors: Laura Piccio; Yuetiva Deming; Jorge L Del-Águila; Laura Ghezzi; David M Holtzman; Anne M Fagan; Chiara Fenoglio; Daniela Galimberti; Barbara Borroni; Carlos Cruchaga Journal: Acta Neuropathol Date: 2016-01-11 Impact factor: 17.088