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Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders

Ayer, Ariane H. BSc*; Wojta, Kevin BSc*; Ramos, Eliana Marisa PhD*; Dokuru, Deepika MHS*; Chen, Jason A. PhD*; Karydas, Anna M. BA; Papatriantafyllou, John D. MD, PhD; Agiomyrgiannakis, Dimitrios MD; Kamtsadeli, Vasiliki BSc; Tsinia, Niki MSc; Sali, Dimitra MD; Gylys, Karen H. PhD*; Agosta, Federica MD, PhD§; Filippi, Massimo MD§; Small, Gary W. MD*; Bennett, David A. MD; Gearing, Marla PhD; Juncos, Jorge L. MD; Kramer, Joel PsyD; Lee, Suzee E. MD; Yokoyama, Jennifer S. PhD; Mendez, Mario F. MD, PhD*; Chui, Helena MD#; Zarow, Chris PhD#; Ringman, John M. MD#,**; Kilic, Ulkan PhD††; Babacan-Yildiz, Gülsen MD‡‡; Levey, Allan MD, PhD; DeCarli, Charles S. MD§§; Cotman, Carl W. PhD∥∥; Boxer, Adam L. MD, PhD; Miller, Bruce L. MD; Coppola, Giovanni MD*,**

Alzheimer Disease & Associated Disorders: October–December 2019 - Volume 33 - Issue 4 - p 327–330
doi: 10.1097/WAD.0000000000000339
Original Articles

Objective: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort.

Methods: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects.

Results: We observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study.

Conclusions: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

*Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine

**Department of Neurology, University of California Los Angeles

#Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles

§§Department of Neurology, School of Medicine, University of California, Davis

∥∥Department of Neurology, School of Medicine, University of California, Irvine

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA

Department of Neurology, Department of Pathology, and Department of Laboratory Medicine, Emory University, Atlanta, GA

Third Age Day Care Center IASIS, Athens, Greece Memory Clinic, Medical Center of Athens, Greece

§Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

††Department of Medical Biology, Faculty of Medicine, University of Health Sciences

‡‡Department of Neurology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey

Department of Neurological Sciences and Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL

A.H.A. and K.W.: contributed equally to this work.

NIMH series. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the “Molecular Genetics of Schizophrenia II” (MGS-2) collaboration. The investigators and co-investigators are: Alan R. Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin, MD (PI); Louisiana State University Health Sciences Center, New Orleans, LA, MH067257, Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870, William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879, C. Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566, Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565, Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson, MD (PI); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman, PhD (PI).

Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study.

Supported by: John Douglas French Alzheimer’s Foundation, NIH Grants R01 AG26938 and RC1 AG035610 (to G.C.). NIH grants P30AG10161, R01AG15819, R01AG17917 (D.A.B.). The project was also supported by NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691), NIA P01 AG1972403 and P50 AG023501 (to B.L.M.), Larry L. Hillblom Foundation Healthy Aging Network 2014-A-004-NET and National Institute on Aging RO1AG032289 (to J.K.). J.A.C. received fellowship support from NINDS (F31 NS084556). The authors acknowledge the support of the Italian Ministry of Health (grant number GR-2010-2303035 and GR-2011-02351217) (to F.A and M.F.), and the Parlow-Solomon Professorship; Stark Fund for Alzheimer’s Research (G.W.S.). P50 AG025688 (to AL). ADC P30 AG10129 (to C.S.D.).

F.A. is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Novartis and Biogen Idec; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. G.W.S. is an advisor/speaker for AARP, Allergan Inc., Avanir, Axovant Sciences Ltd., Forum Pharmaceuticals Inc., Handok Inc., Herbalife International, Janssen Pharmaceuticals Inc., Lily, Lundbeck Inc., Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Co. Ltd., Pfizer Inc., and Theravalues; equity interest in Taumark, LLC. J.A.C. is a founder and major shareholder of Verge Genomics, a San Francisco-based biotechnology company. M.F. is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). The remaining authors declare no conflicts of interest.

Reprints: Giovanni Coppola, MD, Departments of Psychiatry & Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095 (e-mail:

Received October 17, 2018

Accepted May 10, 2019

Online date: September 10, 2019

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