作者
Christina M. Lill,Aina Rengmark,Lasse Pihlstrøm,Isabella Fogh,Aleksey Shatunov,Patrick Sleiman,Li‐San Wang,Tian Liu,Christina Funch Lassen,Esther Meissner,Panagiotis Alexopoulos,Andrea Calvo,Adriano Chiò,Nil Dizdar,Frank Faltraco,Lars Forsgren,Julia Kirchheiner,Alexander Kurz,Jan Petter Larsen,Maria Liebsch,Jan Linder,Karen Morrison,Hans Nissbrandt,Markus Otto,Jens Pahnke,Amanda Partch,Gabriella Restagno,Pálmi V. Jónsson,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,Hákon Hákonarson,Harald Hampel,Christine A. F. Von Arnim,Jörgen H. Olsen,Vivianna M. Van Deerlin,Ammar Al‐Chalabi,Mathias Toft,Beate Ritz,Lars Bertram
摘要
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 (Aβ 42 ) 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 Aβ 42 suggesting that TREM2 's role in AD may involve tau dysfunction.