The TREM2 Variant p.R47H is a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis (I5-2.002)

OBJECTIVE: To determine if p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. BACKGROUND: 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’s disease. Whether the p.R47H variant is a risk factor for ALS is not currently known. METHODS: 923 sporadic ALS subjects and 1854 normal controls 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 was obtained on ALS subjects for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative PCR and compared in spinal cord from 18 ALS subjects, 12 neurologically normal controls, as well as from wildtype and transgenic SOD1 G93A mice. RESULTS: The TREM2 variant p. R47H was more common in subject with ALS than in controls and is therefore a significant risk factor for ALS (OR=2.40; 95%CI=1.29-4.15; p=4.1x10 -3 ). Furthermore, TREM2 expression was increased in spinal cords from ALS patients and SOD1 G93A mice (p=2.8x10 -4 , p=2.8x10 -9 respectively), confirming dysregulated TREM2 in disease. TREM2 expression in human spinal cord was negatively correlated with survival (p=0.04), but not other phenotypic aspects of disease. CONCLUSIONS: The TREM2 p.R47H variant is a potent risk factor for sporadic amyotrophic lateral sclerosis. These findings identify the first genetic influence on neuro-inflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases. Study Supported by: National Institutes of Health (NIH) grants K08-NS075094 (M.B.H.), R01-AG044546 (C.C.), R01-NS078398-02 (T.M.M.), R01-NS069669 (R.H.B.), 5 T32 HL 83822-5 (J.C.), UL1 RR024992, and the Hope Center for Neurological Disorders at Washington University. Disclosure: Dr. Harms has received personal compensation for activities with Genzyme Corp. as a speaker. Dr. Cady has nothing to disclose. Dr. Koval has nothing to disclose. Dr. Benitez has nothing to disclose. Dr. Zaidman has nothing to disclose. Dr. Jockel-Balsarotti has nothing to disclose. Dr. Allred has nothing to disclose. Dr. Baloh has received license fee payments from Genentech, Inc. Dr. Ravits has nothing to disclose. Dr. Simpson has received personal compensation for activities with Groefels. Dr. Simpson has received research support from the CIDP/AIDP International Foundation. Dr. Appel has received personal compensation for activities with Neuraltus Pharmaceuticals, Inc. as a member of their Scientific Advisory Board. Dr. Pestronk has received personal compensation for activities with Athena Diagnostics. Dr. Pestronk has received royalty payments from Athena Diagnostics. Dr. Pestronk holds stock and/or stock options in Johnson & Johnson. Dr. Pestronk has received research support from Knopp, Isis Pharmaceuticals, Sanofi-Aventis Pharmaceuticals Inc., and Prosensa. Dr. Goate has nothing to disclose. Dr. Miller has received research support from Isis Pharmaceuticals. Dr. Cruchaga has nothing to disclose.