TY - JOUR
T1 - TREM2 in neurodegeneration
T2 - Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease
AU - Rayaprolu, Sruti
AU - Mullen, Bianca
AU - Baker, Matt
AU - Lynch, Timothy
AU - Finger, Elizabeth
AU - Seeley, William W.
AU - Hatanpaa, Kimmo J.
AU - Lomen-Hoerth, Catherine
AU - Kertesz, Andrew
AU - Bigio, Eileen H.
AU - Lippa, Carol
AU - Josephs, Keith A.
AU - Knopman, David S.
AU - White, Charles L.
AU - Caselli, Richard
AU - Mackenzie, Ian R.
AU - Miller, Bruce L.
AU - Boczarska-Jedynak, Magdalena
AU - Opala, Grzegorz
AU - Krygowska-Wajs, Anna
AU - Barcikowska, Maria
AU - Younkin, Steven G.
AU - Petersen, Ronald C.
AU - Ertekin-Taner, Nilüfer
AU - Uitti, Ryan J.
AU - Meschia, James F.
AU - Boylan, Kevin B.
AU - Boeve, Bradley F.
AU - Graff-Radford, Neill R.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
AU - Ross, Owen A.
N1 - Funding Information:
We would like to thank all those who have contributed to our research, particularly the patients and families who donated DNA samples for this work. This work was supported by the National Institutes of Health [grant numbers R01 NS078086 (OAR), R01 NS065782 (RR), P50 AG16574 (Mayo ADRC RCP PI; to RR, BFB, NRG-R, DWD and NET), Morris K. Udall Parkinson's Disease Research Center of Excellence P50 NS072187 (OAR, RR, ZKW and DWD), P30 AG012300 (KJH and CLW), RO1 AG026251 (RR), R01 AG18023 (NRG-R and SGY), R01 AG037491 (KAJ), R01AG032990 (NET), AG1657303 (BLM, WWS), AG003949 (DWD), AG13854 (EHB), Cure PSP (DWD), the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (RCP, DWD, NRG-R; SGY), the Alzheimer’s Disease Initiative (ADI) from the State of Florida (DWD), the Consortium for Frontotemporal Dementia Research (RR) and the ALS Therapy Alliance (RR). IRM was supported by the Canadian Institutes of Health Research Operating [#74580] and the Pacific Alzheimer’s Disease Research Foundation. ISGS samples were collected under funding from National Institute of Neurological Disorders and Stroke [grant number R01 NS42733 (JFM)].
PY - 2013
Y1 - 2013
N2 - Background: A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer's disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer's disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results: The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson's disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson's disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions: Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson's disease in addition to Alzheimer's disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
AB - Background: A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer's disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer's disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders. Results: The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson's disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson's disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed. Conclusions: Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson's disease in addition to Alzheimer's disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
KW - Frontotemporal dementia
KW - Genetic association
KW - Parkinson disease
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=84879113935&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879113935&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-8-19
DO - 10.1186/1750-1326-8-19
M3 - Article
C2 - 23800361
AN - SCOPUS:84879113935
VL - 8
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 19
ER -