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Original Investigation |

TREM2 Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis

Janet Cady, BS1; Erica D. Koval, BA1; Bruno A. Benitez, MD2; Craig Zaidman, MD1; Jennifer Jockel-Balsarotti, BS1; Peggy Allred, DPT3; Robert H. Baloh, MD, PhD3,4; John Ravits, MD5; Ericka Simpson, MD6; Stanley H. Appel, MD6; Alan Pestronk, MD1; Alison M. Goate, PhD1,2,7; Timothy M. Miller, MD, PhD1,7; Carlos Cruchaga, PhD2,7; Matthew B. Harms, MD1,7
[+] Author Affiliations
1Department of Neurology, Washington University School of Medicine, St Louis, Missouri
2Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
3Department of Neurology, Cedars Sinai Medical Center, Los Angeles, California
4Department of Neurology, University of California, Los Angeles
5Department of Neurosciences, University of California, San Diego, La Jolla, California
6Department of Neurology, Methodist Neurological Institute, Methodist Research Institute, The Methodist Hospital, Houston, Texas
7Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri
JAMA Neurol. 2014;71(4):449-453. doi:10.1001/jamaneurol.2013.6237.
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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.

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Increased TREM2 Expression in Human Amyotrophic Lateral Sclerosis (ALS) and SOD1G93R Mouse Spinal Cord

A, TREM2 expression was measured by quantitative polymerase chain reaction in lumbar spinal cord sections from 18 individuals with ALS and 12 control individuals and normalized to the geometric mean of 3 endogenous control genes. B, In mice, expression was measured in spinal cord samples from 8 SOD1G93R mice and 6 wild-type littermates, with normalization to an endogenous control. P values were calculated using a 2-tailed t test.

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