title: TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Janet
authors.initials: J
authors.lastname: Cady
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Erica D
authors.initials: ED
authors.lastname: Koval
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Craig
authors.initials: C
authors.lastname: Zaidman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jockel-Balsarotti
authors.affiliation: Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Peggy
authors.initials: P
authors.lastname: Allred
authors.affiliation: Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California4Department of Neurology, University of California, Los Angeles.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.affiliation: Department of Neurology, Methodist Neurological Institute, Methodist Research Institute, The Methodist Hospital, Houston, Texas.
authors.forename: Ericka
authors.initials: E
authors.lastname: Simpson
authors.affiliation: Department of Neurology, Methodist Neurological Institute, Methodist Research Institute, The Methodist Hospital, Houston, Texas.
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.affiliation: 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.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010641:Phenotype; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C000606290:SOD1 protein, human; C498715:TREM2 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1