TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease

Sruti Rayaprolu; Bianca Mullen; Matt Baker; Timothy Lynch; Elizabeth Finger; William W. Seeley; Kimmo J. Hatanpaa; Catherine Lomen-Hoerth; Andrew Kertesz; Eileen H. Bigio; Carol Lippa; Keith A. Josephs; David S. Knopman; Charles L. White; Richard Caselli; Ian R. Mackenzie; Bruce L. Miller; Magdalena Boczarska-Jedynak; Grzegorz Opala; Anna Krygowska-Wajs; Maria Barcikowska; Steven G. Younkin; Ronald C. Petersen; Nilüfer Ertekin-Taner; Ryan J. Uitti; James F. Meschia; Kevin B. Boylan; Bradley F. Boeve; Neill R. Graff-Radford; Zbigniew K. Wszolek; Dennis W. Dickson; Rosa Rademakers; Owen A. Ross

doi:10.1186/1750-1326-8-19

TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease

Sruti Rayaprolu, Bianca Mullen, Matt Baker, Timothy Lynch, Elizabeth Finger, William W. Seeley, Kimmo J. Hatanpaa, Catherine Lomen-Hoerth, Andrew Kertesz, Eileen H. Bigio, Carol Lippa, Keith A. Josephs, David S. Knopman, Charles L. White, Richard Caselli, Ian R. Mackenzie, Bruce L. Miller, Magdalena Boczarska-Jedynak, Grzegorz Opala, Anna Krygowska-WajsMaria Barcikowska, Steven G. Younkin, Ronald C. Petersen, Nilüfer Ertekin-Taner, Ryan J. Uitti, James F. Meschia, Kevin B. Boylan, Bradley F. Boeve, Neill R. Graff-Radford, Zbigniew K. Wszolek, Dennis W. Dickson, Rosa Rademakers, Owen A. Ross

Research output: Contribution to journal › Article › peer-review

214 Scopus citations

Abstract

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.

Original language	English (US)
Article number	19
Journal	Molecular neurodegeneration
Volume	8
Issue number	1
DOIs	https://doi.org/10.1186/1750-1326-8-19
State	Published - 2013

Keywords

Frontotemporal dementia
Genetic association
Parkinson disease
TREM2

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

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Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., Lippa, C., Josephs, K. A., Knopman, D. S., White, C. L., Caselli, R., Mackenzie, I. R., Miller, B. L., Boczarska-Jedynak, M., Opala, G., ... Ross, O. A. (2013). TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Molecular neurodegeneration, 8(1), [19]. https://doi.org/10.1186/1750-1326-8-19

TREM2 in neurodegeneration : Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. / Rayaprolu, Sruti; Mullen, Bianca; Baker, Matt; Lynch, Timothy; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Josephs, Keith A.; Knopman, David S.; White, Charles L.; Caselli, Richard; Mackenzie, Ian R.; Miller, Bruce L.; Boczarska-Jedynak, Magdalena; Opala, Grzegorz; Krygowska-Wajs, Anna; Barcikowska, Maria; Younkin, Steven G.; Petersen, Ronald C.; Ertekin-Taner, Nilüfer; Uitti, Ryan J.; Meschia, James F.; Boylan, Kevin B.; Boeve, Bradley F.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Dickson, Dennis W.; Rademakers, Rosa; Ross, Owen A.

In: Molecular neurodegeneration, Vol. 8, No. 1, 19, 2013.

Research output: Contribution to journal › Article › peer-review

Rayaprolu, S, Mullen, B, Baker, M, Lynch, T, Finger, E, Seeley, WW, Hatanpaa, KJ, Lomen-Hoerth, C, Kertesz, A, Bigio, EH, Lippa, C, Josephs, KA, Knopman, DS, White, CL, Caselli, R, Mackenzie, IR, Miller, BL, Boczarska-Jedynak, M, Opala, G, Krygowska-Wajs, A, Barcikowska, M, Younkin, SG, Petersen, RC, Ertekin-Taner, N, Uitti, RJ, Meschia, JF, Boylan, KB, Boeve, BF, Graff-Radford, NR, Wszolek, ZK, Dickson, DW, Rademakers, R & Ross, OA 2013, 'TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease', Molecular neurodegeneration, vol. 8, no. 1, 19. https://doi.org/10.1186/1750-1326-8-19

Rayaprolu, Sruti ; Mullen, Bianca ; Baker, Matt ; Lynch, Timothy ; Finger, Elizabeth ; Seeley, William W. ; Hatanpaa, Kimmo J. ; Lomen-Hoerth, Catherine ; Kertesz, Andrew ; Bigio, Eileen H. ; Lippa, Carol ; Josephs, Keith A. ; Knopman, David S. ; White, Charles L. ; Caselli, Richard ; Mackenzie, Ian R. ; Miller, Bruce L. ; Boczarska-Jedynak, Magdalena ; Opala, Grzegorz ; Krygowska-Wajs, Anna ; Barcikowska, Maria ; Younkin, Steven G. ; Petersen, Ronald C. ; Ertekin-Taner, Nilüfer ; Uitti, Ryan J. ; Meschia, James F. ; Boylan, Kevin B. ; Boeve, Bradley F. ; Graff-Radford, Neill R. ; Wszolek, Zbigniew K. ; Dickson, Dennis W. ; Rademakers, Rosa ; Ross, Owen A. / TREM2 in neurodegeneration : Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. In: Molecular neurodegeneration. 2013 ; Vol. 8, No. 1.

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title = "TREM2 in neurodegeneration: Evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease",

abstract = "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.",

keywords = "Frontotemporal dementia, Genetic association, Parkinson disease, TREM2",

author = "Sruti Rayaprolu and Bianca Mullen and Matt Baker and Timothy Lynch and Elizabeth Finger and Seeley, {William W.} and Hatanpaa, {Kimmo J.} and Catherine Lomen-Hoerth and Andrew Kertesz and Bigio, {Eileen H.} and Carol Lippa and Josephs, {Keith A.} and Knopman, {David S.} and White, {Charles L.} and Richard Caselli and Mackenzie, {Ian R.} and Miller, {Bruce L.} and Magdalena Boczarska-Jedynak and Grzegorz Opala and Anna Krygowska-Wajs and Maria Barcikowska and Younkin, {Steven G.} and Petersen, {Ronald C.} and Nil{\"u}fer Ertekin-Taner and Uitti, {Ryan J.} and Meschia, {James F.} and Boylan, {Kevin B.} and Boeve, {Bradley F.} and Graff-Radford, {Neill R.} and Wszolek, {Zbigniew K.} and Dickson, {Dennis W.} and Rosa Rademakers and Ross, {Owen A.}",

year = "2013",

doi = "10.1186/1750-1326-8-19",

language = "English (US)",

volume = "8",

journal = "Molecular Neurodegeneration",

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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.

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

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