Alzheimers Dement 2017 Jun 8;13(6):663-673. Epub 2016 Dec 8.
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA. Electronic address:
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 and 4.6 × 10, respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10 and 3.5 × 10, Bonferroni-corrected P = 6.7 × 10 and 7.1 × 10, 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.