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.
Keywords: Alzheimer's disease; Regulatory variant; TREM2; TREML1; eQTL.
Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.