A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jalz.2016.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462884PMC
June 2017
98 Reads

Publication Analysis

Top Keywords

treml1 trem2
12
expression quantitative
8
risk increased
8
increased treml1
8
quantitative trait
8
trait locus
8
trem2 brain
8
gene cluster
8
alzheimer's disease
8
regulatory variant
8
trem gene
8
cortex cerebellum
4
genome-wide association
4
neuropathologically diagnosed
4
35 × 10 bonferroni-corrected
4
cerebellum ∼400
4
point rs9357347
4
locus analysisresults
4
uncorrected p = 34 × 10
4
variant dnase
4

Similar Publications