作者
Rita Guerreiro,Mariet Allen,Jeremy D. Burgess,Xue Wang,Samantha L. Strickland,Shivani Aryal,Joanna Siuda,Michaela Kachadoorian,Markus M. Nöthen,Curtis Younkin,Asha Nair,Chen Wang,Pritha Chanana,Daniel Serie,Thuy Nguyen,Sarah Lincoln,Kimberly G. Malphrus,Kevin Morgan,Todd E. Golde,Nathan D. Price,Yeunjoo E. Song,Philip L. De Jager,David A. Bennett,Yan W. Asmann,Julia E. Crook,Peter St George‐Hyslop,Caroline Graff,Dennis W. Dickson,Stéphanie Debette,Nilüfer Ertekin‐Taner
摘要
Abstract Introduction We hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid ( TREM ) gene cluster influence disease through gene expression. Methods Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. Results A variant within a DNase hypersensitive site 5′ of TREM2 , rs9357347‐C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10 −3 and 4.6 × 10 −2 , respectively). Meta‐analysis on expression quantitative trait locus results from three independent data sets ( n = 1006) confirmed these associations (uncorrected P = 3.4 × 10 −2 and 3.5 × 10 −3 , Bonferroni‐corrected P = 6.7 × 10 −2 and 7.1 × 10 −3 , respectively). Discussion Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome‐wide association study meta‐analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.