The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Christina M. Lill; Aina Rengmark; Lasse Pihlstrøm; Isabella Fogh; Aleksey Shatunov; Patrick M. Sleiman; Li San Wang; Tian Liu; Christina F. Lassen; Esther Meissner; Panos Alexopoulos; Andrea Calvo; Adriano Chio; Nil Dizdar; Frank Faltraco; Lars Forsgren; Julia Kirchheiner; Alexander Kurz; Jan P. Larsen; Maria Liebsch; Jan Linder; Karen E. Morrison; Hans Nissbrandt; Markus Otto; Jens Pahnke; Amanda Partch; Gabriella Restagno; Dan Rujescu; Cathrin Schnack; Christopher E. Shaw; Pamela J. Shaw; Hayrettin Tumani; Ole Bjørn Tysnes; Otto Valladares; Vincenzo Silani; Leonard H. van den Berg; Wouter van Rheenen; Jan H. Veldink; Ulman Lindenberger; Elisabeth Steinhagen-Thiessen; Stefan Teipel; Robert Perneczky; Hakon Hakonarson; Harald Hampel; Christine A F von Arnim; Jørgen H. Olsen; Vivianna M. Van Deerlin; Ammar Al-Chalabi; Mathias Toft; Beate Ritz; Lars Bertram

doi:10.1016/j.jalz.2014.12.009

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Christina M. Lill^*, Aina Rengmark, Lasse Pihlstrøm, Isabella Fogh, Aleksey Shatunov, Patrick M. Sleiman, Li San Wang, Tian Liu, Christina F. Lassen, Esther Meissner, Panos Alexopoulos, Andrea Calvo, Adriano Chio, Nil Dizdar, Frank Faltraco, Lars Forsgren, Julia Kirchheiner, Alexander Kurz, Jan P. Larsen, Maria LiebschJan Linder, Karen E. Morrison, Hans Nissbrandt, Markus Otto, Jens Pahnke, Amanda Partch, Gabriella Restagno, Dan Rujescu, Cathrin Schnack, Christopher E. Shaw, Pamela J. Shaw, Hayrettin Tumani, Ole Bjørn Tysnes, Otto Valladares, Vincenzo Silani, Leonard H. van den Berg, Wouter van Rheenen, Jan H. Veldink, Ulman Lindenberger, Elisabeth Steinhagen-Thiessen, Stefan Teipel, Robert Perneczky, Hakon Hakonarson, Harald Hampel, Christine A F von Arnim, Jørgen H. Olsen, Vivianna M. Van Deerlin, Ammar Al-Chalabi, Mathias Toft, Beate Ritz, Lars Bertram

^*Corresponding author for this work

Clinical Sciences

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

108 Citations (Scopus)

Abstract

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

Original language	English
Pages (from-to)	1407-1416
Journal	Alzheimer's & Dementia
Volume	11
Issue number	12
Early online date	30 Apr 2015
DOIs	https://doi.org/10.1016/j.jalz.2014.12.009
Publication status	Published - Dec 2015

Keywords

Alzheimer disease
Amyotrophic lateral sclerosis
Frontotemporal lobar degeneration
Genetic association
GWAS
Imputation
Meta-analysis
Neurodegenerative disease
Parkinson disease
R47H
Rare variant
Rs75932628
TREM2

ASJC Scopus subject areas

Clinical Neurology
Developmental Neuroscience
Cellular and Molecular Neuroscience
Psychiatry and Mental health
Geriatrics and Gerontology
Epidemiology
Health Policy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L. S., Liu, T., Lassen, C. F., Meissner, E., Alexopoulos, P., Calvo, A., Chio, A., Dizdar, N., Faltraco, F., Forsgren, L., Kirchheiner, J., Kurz, A., Larsen, J. P., ... Bertram, L. (2015). The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimer's & Dementia, 11(12), 1407-1416. https://doi.org/10.1016/j.jalz.2014.12.009

@article{bf0dc3b3b5444d8da782e34bb2ab0e8a,

title = "The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease",

abstract = "A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.",

keywords = "Alzheimer disease, Amyotrophic lateral sclerosis, Frontotemporal lobar degeneration, Genetic association, GWAS, Imputation, Meta-analysis, Neurodegenerative disease, Parkinson disease, R47H, Rare variant, Rs75932628, TREM2",

author = "Lill, {Christina M.} and Aina Rengmark and Lasse Pihlstr{\o}m and Isabella Fogh and Aleksey Shatunov and Sleiman, {Patrick M.} and Wang, {Li San} and Tian Liu and Lassen, {Christina F.} and Esther Meissner and Panos Alexopoulos and Andrea Calvo and Adriano Chio and Nil Dizdar and Frank Faltraco and Lars Forsgren and Julia Kirchheiner and Alexander Kurz and Larsen, {Jan P.} and Maria Liebsch and Jan Linder and Morrison, {Karen E.} and Hans Nissbrandt and Markus Otto and Jens Pahnke and Amanda Partch and Gabriella Restagno and Dan Rujescu and Cathrin Schnack and Shaw, {Christopher E.} and Shaw, {Pamela J.} and Hayrettin Tumani and Tysnes, {Ole Bj{\o}rn} and Otto Valladares and Vincenzo Silani and {van den Berg}, {Leonard H.} and {van Rheenen}, Wouter and Veldink, {Jan H.} and Ulman Lindenberger and Elisabeth Steinhagen-Thiessen and Stefan Teipel and Robert Perneczky and Hakon Hakonarson and Harald Hampel and {von Arnim}, {Christine A F} and Olsen, {J{\o}rgen H.} and {Van Deerlin}, {Vivianna M.} and Ammar Al-Chalabi and Mathias Toft and Beate Ritz and Lars Bertram",

year = "2015",

month = dec,

doi = "10.1016/j.jalz.2014.12.009",

language = "English",

volume = "11",

pages = "1407--1416",

journal = "Alzheimer's & Dementia",

issn = "1552-5260",

publisher = "Elsevier",

number = "12",

}

Lill, CM, Rengmark, A, Pihlstrøm, L, Fogh, I, Shatunov, A, Sleiman, PM, Wang, LS, Liu, T, Lassen, CF, Meissner, E, Alexopoulos, P, Calvo, A, Chio, A, Dizdar, N, Faltraco, F, Forsgren, L, Kirchheiner, J, Kurz, A, Larsen, JP, Liebsch, M, Linder, J, Morrison, KE, Nissbrandt, H, Otto, M, Pahnke, J, Partch, A, Restagno, G, Rujescu, D, Schnack, C, Shaw, CE, Shaw, PJ, Tumani, H, Tysnes, OB, Valladares, O, Silani, V, van den Berg, LH, van Rheenen, W, Veldink, JH, Lindenberger, U, Steinhagen-Thiessen, E, Teipel, S, Perneczky, R, Hakonarson, H, Hampel, H, von Arnim, CAF, Olsen, JH, Van Deerlin, VM, Al-Chalabi, A, Toft, M, Ritz, B & Bertram, L 2015, 'The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease', Alzheimer's & Dementia, vol. 11, no. 12, pp. 1407-1416. https://doi.org/10.1016/j.jalz.2014.12.009

TY - JOUR

T1 - The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

AU - Lill, Christina M.

AU - Rengmark, Aina

AU - Pihlstrøm, Lasse

AU - Fogh, Isabella

AU - Shatunov, Aleksey

AU - Sleiman, Patrick M.

AU - Wang, Li San

AU - Liu, Tian

AU - Lassen, Christina F.

AU - Meissner, Esther

AU - Alexopoulos, Panos

AU - Calvo, Andrea

AU - Chio, Adriano

AU - Dizdar, Nil

AU - Faltraco, Frank

AU - Forsgren, Lars

AU - Kirchheiner, Julia

AU - Kurz, Alexander

AU - Larsen, Jan P.

AU - Liebsch, Maria

AU - Linder, Jan

AU - Morrison, Karen E.

AU - Nissbrandt, Hans

AU - Otto, Markus

AU - Pahnke, Jens

AU - Partch, Amanda

AU - Restagno, Gabriella

AU - Rujescu, Dan

AU - Schnack, Cathrin

AU - Shaw, Christopher E.

AU - Shaw, Pamela J.

AU - Tumani, Hayrettin

AU - Tysnes, Ole Bjørn

AU - Valladares, Otto

AU - Silani, Vincenzo

AU - van den Berg, Leonard H.

AU - van Rheenen, Wouter

AU - Veldink, Jan H.

AU - Lindenberger, Ulman

AU - Steinhagen-Thiessen, Elisabeth

AU - Teipel, Stefan

AU - Perneczky, Robert

AU - Hakonarson, Hakon

AU - Hampel, Harald

AU - von Arnim, Christine A F

AU - Olsen, Jørgen H.

AU - Van Deerlin, Vivianna M.

AU - Al-Chalabi, Ammar

AU - Toft, Mathias

AU - Ritz, Beate

AU - Bertram, Lars

PY - 2015/12

Y1 - 2015/12

N2 - A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

AB - A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

KW - Alzheimer disease

KW - Amyotrophic lateral sclerosis

KW - Frontotemporal lobar degeneration

KW - Genetic association

KW - GWAS

KW - Imputation

KW - Meta-analysis

KW - Neurodegenerative disease

KW - Parkinson disease

KW - R47H

KW - Rare variant

KW - Rs75932628

KW - TREM2

UR - http://www.scopus.com/inward/record.url?scp=84929104407&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2014.12.009

DO - 10.1016/j.jalz.2014.12.009

M3 - Article

C2 - 25936935

SN - 1552-5260

VL - 11

SP - 1407

EP - 1416

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 12

ER -

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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